US10793561B2 - 1,8-naphthyridinone compounds and uses thereof - Google Patents

1,8-naphthyridinone compounds and uses thereof Download PDF

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US10793561B2
US10793561B2 US16/039,301 US201816039301A US10793561B2 US 10793561 B2 US10793561 B2 US 10793561B2 US 201816039301 A US201816039301 A US 201816039301A US 10793561 B2 US10793561 B2 US 10793561B2
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alkylene
compound
halogen
alkyl
pharmaceutically acceptable
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US20190023702A1 (en
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Son Minh Pham
Jiyun Chen
Amantullah ANSARI
Pradeep S. JADHAVAR
Varshavekumar S. PATIL
Farha KHAN
Sreekanth A. Ramachandran
Anil Kumar AGARWAL
Sarvajit Chakravarty
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Nuvation Bio Inc
Sparcbio LLC
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Nuvation Bio Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • This disclosure relates generally to therapeutics for treatment mediated through a G-protein-coupled receptor (GPCR) signaling pathway and, more particularly, to compounds that inhibit an adenosine receptor (such as an A 2A antagonist).
  • GPCR G-protein-coupled receptor
  • the disclosure also provides pharmaceutically acceptable compositions comprising such compounds and methods of using the compounds or compositions in the treatment of a disease associated with a GPCR signaling pathway.
  • Adenosine receptors are distributed throughout the body and are responsible for numerous biological functions.
  • the seven trans-membrane G-protein-coupled receptors (GPCRs) have been divided into four different subtypes: A 1 , A 2A , A 2B , and A 3 .
  • the A 2A and A 2B ARs stimulate activity of the adenylyl cyclase, inducing an increase of cAMP levels.
  • a 2A ARs have a distinct tissue localization, different biochemical pathways, and specific pharmacological profiles.
  • Adenosine is one of the human body's most important neuromodulators in both the central and the peripheral nervous systems. Adenosine is released from tumor cells and its concentration in the extracellular fluid of tumors can reach immunosuppressive levels (Blay et al. (1997), Cancer Res., 57(13), pp. 2602-5). The extracellular fluid of solid carcinomas contains immunosuppressive concentrations of adenosine. Id. This increase in adenosine concentration is a result of increases in CD73 (ecto-5′-nucleotidase) and CD39 (nucleoside triphosphate dephosphorylase) enzymes, which are responsible for directly catabolizing ATP into adenosine.
  • CD73 ecto-5′-nucleotidase
  • CD39 nucleoside triphosphate dephosphorylase
  • upregulations are triggered by hypoxia and the generation of HIF-1 ⁇ .
  • High levels of adenosine around tumor cells act to regulate multiple immune cells (e.g., CD4 + T-cells and cytotoxic CD8 + T-cells) via activation of multiple adenosine receptor subtypes, but particularly A 2A receptors, resulting the suppressing of pro-inflammatory activities and upregulation of anti-inflammatory molecules and immunoregulatory cells (Kumar et al. (2013), Adenosine as an endogenous immunoregulator in cancer pathogenesis: where to go?
  • Adenosine whose concentration increases within hypoxic regions of solid tumors, has been recognized as being able to interfere with the recognition of tumor cells by cytolytic effector cells of the immune system. (Tuite and Riss (2013). Recent developments in the pharmacological treatment of Parkinson's disease. Expert Opin. Investig. Drugs, 12(8) pp 1335-52, Popoli et al. (2002).
  • Blockade of striatal adenosine A 2A receptor reduces, through a presynaptic mechanism, quinolinic acid-induced excitotoxicity: possible relevance to neuroprotective interventions in neurodegenerative diseases of the striatum, J. Neurosci, 22(5) pp. 1967-75, Gessi et al. (2011). Adenosine receptors and cancer. Biochim Biophys Acta, 1808(5), pp. 1400-12).
  • a 2A and A 3 subtypes appear promising targets for therapeutic development.
  • activation of A 2A receptors leads to immunosuppressive effects, which decreases anti-tumoral immunity and thereby encourages tumor growth.
  • the A 2B receptor is another potential target for therapeutic development. Autocrine/paracrine stimulation of A 2B expressed on tumor cells is believed to enhance their metastatic potential and A 2B blockade may reduce tumor metastasis in an immune-independent manner (Beavis et al. (2013). Blockade of A 2A receptors potently suppresses the metabolism of CD73 + Tumors. Proc. Natl. Acad. Sci., 110(36) pp. 14711-6). A 2B expression also correlates with relapse-free survival (RFS) in triple negative breast cancer suggesting that this pathway may be clinically relevant.
  • RFS relapse-free survival
  • a 2B blockade also has the potential to modulate the immunosuppressive properties of tumor-associated immune cells including dendritic cells and myeloid-derived suppressor cells (MDSCs) (Cekic et al. (2011). Adenosine A2B receptor blockade slows growth of bladder and breast tumors. J. Immunol. 188(1), pp. 198-205; Sorrentino et al. (2015). Myeloid-derived suppressor cells contribute to A 2B adenosine receptor-induced VEGF production and angiogenesis in a mouse melanoma model. Oncotarget 6(29), pp. 27478-89; Iannone et al. (2013). Blockade of A 2B adenosine receptor reduces tumor growth and immune suppression mediated by myeloid-derived suppressor cells in a mouse model of melanoma. Neoplasia, 15(12), pp. 1400-9.
  • MDSCs myeloid-derived suppressor cells
  • the compound of the formula (I), or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing is of the formula (II) or (III), or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, as detailed herein.
  • the compound of the formula (I), or a tautomer thereof, or a salt of any of the foregoing is of the formula (II).
  • the compound of the formula (I), or a tautomer thereof, or a salt of any of the foregoing is of the formula (III).
  • a disease such as a proliferative disease
  • a disease such as a proliferative disease
  • the compound of formula (I) or a tautomer thereof, or a salt of any of the foregoing is administered to the individual in combination with another therapeutic agent.
  • the compound of formula (I) or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing is administered to the individual in combination with another therapeutic agent.
  • the compound of formula (I) or a salt thereof is a compound of the formula (II) or (III) or a tautomer thereof, or a or a salt of any of the foregoing.
  • the compound of formula (I) or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing is a compound of the formula (II) or (III), or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
  • compositions comprising (A) a compound detailed herein, such as a compound of formula (I) or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a compound of formula (II) or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a compound of formula (III) or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (B) a pharmaceutically acceptable carrier or excipient.
  • a compound detailed herein such as a compound of formula (I) or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a compound of formula (II) or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a compound of formula (III) or a tautomer or isomer thereof, or a pharmaceutically acceptable
  • compositions comprising (A) a compound detailed herein, such as a compound of formula (I) or a tautomer thereof, or a or a salt of any of the foregoing, or a compound of formula (II) or a tautomer thereof, or a or a salt of any of the foregoing, or a compound of formula (III) or a tautomer thereof, or a or a salt of any of the foregoing, and (B) a pharmaceutically acceptable carrier or excipient.
  • Kits comprising a compound detailed herein or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing and instructions for use are also provided.
  • Alkenyl refers to an unsaturated linear or branched univalent hydrocarbon chain or combination thereof, having at least one site of olefinic unsaturation (i.e., having at least one moiety of the formula C ⁇ C) and having the number of carbon atoms designated (i.e., C 2 -C 10 means two to ten carbon atoms).
  • the alkenyl group may be in “cis” or “trans” configurations, or alternatively in “E” or “Z” configurations.
  • Particular alkenyl groups are those having 2 to 20 carbon atoms (a “C 2 -C 20 alkenyl”), having 2 to 8 carbon atoms (a “C 2 -C 8 alkenyl”), having 2 to 6 carbon atoms (a “C 2 -C 6 alkenyl”), or having 2 to 4 carbon atoms (a “C 2 -C 4 alkenyl”).
  • alkyl refers to and includes saturated linear and branched univalent hydrocarbon structures and combination thereof, having the number of carbon atoms designated (i.e., C 1 -C 10 means one to ten carbons). Particular alkyl groups are those having 1 to 20 carbon atoms (a “C 1 -C 20 alkyl”).
  • alkyl examples include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
  • Alkynyl refers to an unsaturated linear or branched univalent hydrocarbon chain or combination thereof, having at least one site of acetylenic unsaturation (i.e., having at least one moiety of the formula C ⁇ C) and having the number of carbon atoms designated (i.e., C 2 -C 10 means two to ten carbon atoms).
  • cycloalkyl or “carbocycle” are used interchangeably and refer to and include cyclic univalent hydrocarbon structures, which may be fully saturated, mono- or polyunsaturated, but which are non-aromatic, having the number of carbon atoms designated (e.g., C 1 -C 10 means one to ten carbons).
  • Cycloalkyl or carbocycle groups can consist of one ring, such as cyclohexyl, or multiple rings, such as adamantyl, but excludes aryl groups.
  • a cycloalkyl or carbocycle comprising more than one ring may be fused, spiro or bridged, or combinations thereof.
  • Halo or “halogen” refers to elements of the Group 17 series having atomic number 9 to 85. Preferred halo groups include fluoro, chloro, bromo and iodo. Where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached, e.g., dihaloaryl, dihaloalkyl, trihaloaryl etc. refer to aryl and alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be but are not necessarily the same halo; thus 4-chloro-3-fluorophenyl is within the scope of dihaloaryl.
  • perhaloalkyl An alkyl group in which each hydrogen is replaced with a halo group is referred to as a “perhaloalkyl.”
  • a preferred perhaloalkyl group is trifluoroalkyl (—CF 3 ).
  • perhaloalkoxy refers to an alkoxy group in which a halogen takes the place of each H in the hydrocarbon making up the alkyl moiety of the alkoxy group.
  • An example of a perhaloalkoxy group is trifluoromethoxy (—OCF 3 ).
  • heteroaryl refers to and includes unsaturated aromatic cyclic groups having from 1 to 10 annular carbon atoms and at least one annular heteroatom, including but not limited to heteroatoms such as nitrogen, oxygen and sulfur, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized.
  • a heteroaryl group can be attached to the remainder of the molecule at an annular carbon or at an annular heteroatom.
  • Heteroaryl may contain additional fused rings (e.g., from 1 to 3 rings), including additionally fused aryl, heteroaryl, cycloalkyl, and/or heterocyclyl rings.
  • heteroaryl groups include, but are not limited to, pyridyl, pyrimidyl, thiophenyl, furanyl, thiazolyl, and the like.
  • heteroaryl groups also include, but are not limited to, pyridyl, pyrimidyl, thiophenyl, furanyl, thiazolyl, oxazolyl, isoxazolyl, thiophenyl, pyrrolyl, pyrazolyl, 1,3,4-oxadiazolyl, imidazolyl, isothiazolyl, triazolyl, 1,3,4-thiadiazolyl, tetrazolyl, benzofuranyl, benzothiophenyl, pyrazolopyridinyl, indazolyl, benzothiazolyl, benzooxazolyl or benzoimidazolyl and the like
  • a heteroaryl containing at least one additional fused ring that is nonaromatic is attached to the parent structure at an annular atom of the additional ring.
  • a heteroaryl containing at least one additional ring that is nonaromatic is attached to the parent structure at an annular atom of the aromatic ring.
  • Optionally substituted unless otherwise specified means that a group may be unsubstituted or substituted by one or more (e.g., 1, 2, 3, 4 or 5) of the substituents listed for that group in which the substituents may be the same of different.
  • an optionally substituted group has one substituent.
  • an optionally substituted group has two substituents.
  • an optionally substituted group has three substituents.
  • an optionally substituted group has four substituents.
  • an optionally substituted group has 1 to 2, 2 to 5, 3 to 5, 2 to 3, 2 to 4, 3 to 4, 1 to 3, 1 to 4 or 1 to 5 substituents.
  • an “effective dosage” or “effective amount” of compound or salt thereof or pharmaceutical composition is an amount sufficient to effect beneficial or desired results.
  • beneficial or desired results include results such as eliminating or reducing the risk, lessening the severity of, or delaying the onset of the disease, including biochemical, histological and/or behavioral symptoms of the disease, its complications and intermediate pathological phenotypes presenting during development of the disease.
  • beneficial or desired results include ameliorating, palliating, lessening, delaying or decreasing one or more symptoms resulting from the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, enhancing effect of another medication such as via targeting, delaying the progression of the disease, and/or prolonging survival.
  • an effective amount can be administered in one or more administrations, in the case of cancer, the effective amount of the drug or composition may: (i) reduce the number of cancer cells; (ii) reduce tumor size; (iii) inhibit, retard, slow to some extent and preferably stop cancer cell infiltration into peripheral organs; (iv) inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; (v) inhibit tumor growth; (vi) prevent or delay occurrence and/or recurrence of tumor; and/or (vii) relieve to some extent one or more of the symptoms associated with the cancer.
  • An effective dosage can be administered in one or more administrations.
  • references to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X”.
  • R 1 is H or C 1 -C 6 alkyl wherein the C 1 -C 6 alkyl of R 1 is optionally substituted with oxo or R a ;
  • R 2 and R 4 are each independently H, R b or oxo;
  • R 3 and R 5 are each independently H or R c ;
  • each R a , R b , and R c is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, —CN, —OR 8 , —SR 8 , —NR 9 R 10 , —NO 2 , —C ⁇ NH(OR 8 ), —C(O)R 8 , —OC(O)R 8 , —C(O)OR 8 , —C(O)NR 9 R 10 , —OC(O)NR 9 R 10 , —NR 8 C(O)R 9 , —NR 8 C(O)OR 9 , —NR 8 C(O)NR 9 R 10 , —S(O)R 8 , —S(O) 2 R 8 , —NR 8 S(O)R 9 , —C(O)NR 8 S(O)R 9 , —NR 8 S(O) 2 R 9 , —C(O)
  • R 4 is oxo
  • A is C 6 -C 12 aryl, 5- to 10-membered heteroaryl, 9- to 10-membered carbocycle, or 9- to 10-membered heterocycle, wherein the C 6 -C 12 aryl, 5- to 10-membered heteroaryl, 9- to 10-membered carbocycle, or 9- to 10-membered heterocycle of A is optionally further substituted with R 6 ;
  • B is phenyl, 5- to 6-membered heteroaryl, 5- to 6-membered carbocycle, 5- to 6-membered heterocycle, or 9- to 10-membered heteroaryl, wherein the phenyl, 5- to 6-membered heteroaryl, 5- to 6-membered carbocycle, 5- to 6-membered heterocycle, or 9- to 10-membered heteroaryl of B is optionally further substituted with R 7 ;
  • B is 5- to 6-membered heterocycle, A is other than phenyl or pyridyl optionally further substituted with R 7 ;
  • each R 6 and R 7 is independently oxo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, —CN, —OR 8 , —SR 8 , —NR 9 R 10 , —NO 2 , —C ⁇ NH(OR 8 ), —C(O)R 8 , —OC(O)R 8 , —C(O)OR 8 , —C(O)NR 9 R 10 , —OC(O)NR 9 R 10 , —NR 8 C(O)R 9 , —NR 8 C(O)OR 9 , —NR 8 C(O)NR 9 R 10 , —S(O)R 8 , —S(O) 2 R 8 , —NR 8 S(O)R 9 , —C(O)NR 8 S(O)R 9 , —NR 8 S(O) 2 R 9 , —C(O)NR 8 S(
  • each R 8 is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 6 -C 14 aryl, 5-6-membered heteroaryl, 3-6-membered heterocyclyl, —(C 1 -C 3 alkylene)(C 3 -C 6 cycloalkyl), —(C 1 -C 3 alkylene)(C 6 -C 14 aryl), —(C 1 -C 3 alkylene)(5-6-membered heteroaryl), or —(C 1 -C 3 alkylene)(3-6-membered heterocyclyl), wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 6 -C 14 aryl, 5-6-membered heteroaryl,
  • R 9 and R 10 are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 6 -C 14 aryl, 5-6-membered heteroaryl, 3-6 membered heterocyclyl, —(C 1 -C 3 alkylene)NR 11 R 12 , —(C 1 -C 3 alkylene)(C 3 -C 6 cycloalkyl), —(C 1 -C 3 alkylene)(3-6-membered heterocyclyl), —(C 1 -C 3 alkylene)(5-6-membered heteroaryl) or —(C 1 -C 3 alkylene)(C 6 aryl), wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 6 -
  • R 11 and R 12 are each independently hydrogen, C 1 -C 6 alkyl optionally substituted by halogen or oxo, C 2 -C 6 alkenyl optionally substituted by halogen or oxo, or C 2 -C 6 alkynyl optionally substituted by halogen or oxo; or R 11 and R 12 are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo or C 1 -C 6 alkyl optionally substituted by halogen or oxo; and
  • R 1 is H or C 1 -C 6 alkyl wherein the C 1 -C 6 alkyl of R 1 is optionally substituted with oxo or R a ;
  • R 2 and R 4 are each independently H, R b or oxo;
  • R 3 and R 5 are each independently H or R c ;
  • each R a , R b , and R c is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, —CN, —OR 8 , —SR 8 , —NR 9 R 10 , —NO 2 , —C ⁇ NH(OR 8 ), —C(O)R 8 , —OC(O)R 8 , —C(O)OR 8 , —C(O)NR 9 R 10 , —OC(O)NR 9 R 10 , —NR 8 C(O)R 9 , —NR 8 C(O)OR 9 , —NR 8 C(O)NR 9 R 10 , —S(O)R 8 , —S(O) 2 R 8 , —NR 8 S(O)R 9 , —C(O)NR 8 S(O)R 9 , —NR 8 S(O) 2 R 9 , —C(O)
  • R 4 is oxo
  • A is C 6 -C 12 aryl, 5- to 10-membered heteroaryl, 9- to 10-membered carbocycle, or 9- to 10-membered heterocycle, wherein the C 6 -C 12 aryl, 5- to 10-membered heteroaryl, 9- to 10-membered carbocycle, or 9- to 10-membered heterocycle of A is optionally further substituted with R 6 ;
  • B is phenyl, 5- to 6-membered heteroaryl, 5- to 6-membered carbocycle, 5- to 6-membered heterocycle, or 9- to 10-membered heteroaryl, wherein the phenyl, 5- to 6-membered heteroaryl, 5- to 6-membered carbocycle, 5- to 6-membered heterocycle, or 9- to 10-membered heteroaryl of B is optionally further substituted with R 7 ;
  • B is 5- to 6-membered heterocycle, A is other than phenyl or pyridyl optionally further substituted with R 7 ;
  • each R 6 and R 7 is independently oxo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, —CN, —OR 8 , —SR 8 , —NR 9 R 10 , —NO 2 , —C ⁇ NH(OR 8 ), —C(O)R 8 , —OC(O)R 8 , —C(O)OR 8 , —C(O)NR 9 R 10 , —OC(O)NR 9 R 10 , —NR 8 C(O)R 9 , —NR 8 C(O)OR 9 , —NR 8 C(O)NR 9 R 10 , —S(O)R 8 , —S(O) 2 R 8 , —NR 8 S(O)R 9 , —C(O)NR 8 S(O)R 9 , —NR 8 S(O) 2 R 9 , —C(O)NR 8 S(
  • R 8 is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 6 -C 14 aryl, 5-6-membered heteroaryl or 3-6-membered heterocyclyl, wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 6 -C 14 aryl, 5-6-membered heteroaryl and 3-6-membered heterocyclyl are independently optionally substituted by halogen, oxo, —CN, —OR 13 , —NR 13 R 14 , —P(O)(OR 13 )(OR 14 ), phenyl optionally substituted by halogen, or C 1 -C 6 alkyl optionally substituted by halogen, —OH or oxo;
  • R 9 and R 10 are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 6 -C 14 aryl, 5-6-membered heteroaryl or 3-6 membered heterocyclyl, wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 6 -C 14 aryl, 5-6-membered heteroaryl and 3-6 membered heterocyclyl are independently optionally substituted by halogen, oxo, —CN, —OR 13 , —NR 13 R 14 or C 1 -C 6 alkyl optionally substituted by halogen, —OH or oxo;
  • R 11 and R 12 are each independently hydrogen, C 1 -C 6 alkyl optionally substituted by halogen or oxo, C 2 -C 6 alkenyl optionally substituted by halogen or oxo, or C 2 -C 6 alkynyl optionally substituted by halogen or oxo;
  • R 13 and R 14 are each independently hydrogen, C 1 -C 6 alkyl optionally substituted by halogen or oxo, C 2 -C 6 alkenyl optionally substituted by halogen or oxo, or C 2 -C 6 alkynyl optionally substituted by halogen or oxo;
  • A is selected from the group consisting of C 6 -C 12 aryl and 5- to 10-membered heteroaryl, wherein the C 6 -C 12 aryl and 5- to 10-membered heteroaryl of A is optionally further substituted with R 6 .
  • B is selected from the group consisting of phenyl and 5- to 6-membered heteroaryl, wherein the phenyl and 5- to 6-membered heteroaryl of B is optionally further substituted with R 7 .
  • A is selected from the group consisting of C 6 -C 12 aryl and 5- to 10-membered heteroaryl, wherein the C 6 -C 12 aryl and 5- to 10-membered heteroaryl of A is optionally further substituted with R 6 and B is selected from the group consisting of phenyl and 5- to 6-membered heteroaryl, wherein the phenyl and 5- to 6-membered heteroaryl of B is optionally further substituted with R 7 .
  • R a , R b , and R c are independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, —CN, —OR 8 , —SR 8 , —NR 9 R 10 , —C(O)NR 9 R 10 , —NR 8 C(O)R 9 , —NR 8 C(O)NR 9 R 10 , —S(O)R 8 , —S(O) 2 R, —NR 8 S(O)R 9 , —NR 8 S(O) 2 R 9 , —S(O)NR 9 R 10 , —S(O) 2 NR 9 R 10 , C 3 -C 6 cycloalkyl, 3-12-membered heterocyclyl, 5- to 10-membered heteroaryl or C 6 -C 14 aryl.
  • R a , R b , and R c are independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, —CN, —OR 8 , —SR 8 , —NR 9 R 10 , —C(O)NR 9 R 10 , —NR 8 C(O)R 9 , C 3 -C 6 cycloalkyl, 3-12-membered heterocyclyl, 5- to 10-membered heteroaryl or C 6 -C 14 aryl.
  • R a , R b , and R c are independently C 1 -C 6 alkyl, halogen, —CN, —OR 8 , —SR 8 or —NR 9 R 10 ,
  • R a , R b , and R c are independently —CH 3 , halogen, —CN or —OCH 3 .
  • R 1 is H or methyl.
  • R 5 is H, C 1 -C 6 alkyl, halogen, —CN, or —OR 8 .
  • R 1 , R 2 , R 3 , and R 5 are each H and R 4 is oxo. In some embodiments of the compound of Formula (I), R 1 , R 3 , R 4 , and R 5 are each H and R 2 is oxo.
  • At least one of R 3 , R 4 , and R 5 is not H. In some embodiments, at least one of R 3 , R 4 , and R 5 is C 1 -C 6 alkyl, halogen, C 6 -C 14 aryl, —CN, or —OR 8 . In some embodiments, R 1 , R 3 , R 4 , and R 5 are each H.
  • At least one of R 2 , R 3 , and R 5 is not H. In some embodiments, at least one of R 2 , R 3 , and R 5 is C 1 -C 6 alkyl, halogen, C 6 -C 14 aryl, —CN, or —OR 8 . In some embodiments, R 1 , R 2 , R 3 , and R 5 are each H.
  • R 1 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, —CN, —OR 8 , —SR 8 , —NR 9 R 10 , —C(O)NR 9 R 10 , —NR 8 C(O)R 9 , —NR 8 C(O)NR 9 R 10 , —S(O)R 8 , —S(O) 2 R 8 , —NR 8 S(O)R 9 , —NR 8 S(O) 2 R 9 , —S(O)NR 9 R 10 , —S(O) 2 NR 9 R 10 , C 3 -C 6 cycloalkyl, 3-12-membered heterocyclyl, 5- to 10-membered heteroaryl or C 6 -C 14 aryl.
  • R 1 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, —CN, —OR 8 , —SR 8 , —NR 9 R 10 , —C(O)NR 9 R 10 , —NR 8 C(O)R 9 , C 3 -C 6 cycloalkyl, 3-12-membered heterocyclyl, 5- to 10-membered heteroaryl or C 6 -C 14 aryl.
  • R 1 is C 1 -C 6 alkyl, halogen, —CN, —OR, —SR 8 or —NR 9 R 10 .
  • R 1 is —CH 3 , halogen, —CN or —OCH 3 .
  • R 1 is H or methyl.
  • R 1 is H, C 1 -C 6 alkyl, halogen, —CN, or —OR 8 .
  • R 1 is H or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), (II), or (III), R 1 is H or methyl. In some embodiments, R 1 is H.
  • R 2 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, —CN, —OR, —SR 8 , —NR 9 R 10 , —C(O)NR 9 R 10 , —NR 8 C(O)R 9 , —NR 8 C(O)NR 9 R 10 , —S(O)R 8 , —S(O) 2 R 8 , —NR 8 S(O)R 9 , —NR 8 S(O) 2 R 9 , —S(O)NR 9 R 10 , —S(O) 2 NR 9 R 10 , C 3 -C 6 cycloalkyl, 3-12-membered heterocyclyl, 5- to 10-membered heteroaryl or C 6 -C 14 aryl.
  • R 2 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, —CN, —OR 8 , —SR 8 , —NR 9 R 10 , —C(O)NR 9 R 10 , —NR 8 C(O)R 9 , C 3 -C 6 cycloalkyl, 3-12-membered heterocyclyl, 5- to 10-membered heteroaryl or C 6 -C 14 aryl.
  • R 2 is C 1 -C 6 alkyl, halogen, —CN, —OR 8 , —SR 8 or —NR 9 R 10 .
  • R 2 is —CH 3 , halogen, —CN or —OCH 3 .
  • R 2 is H or methyl.
  • R 2 is H, C 1 -C 6 alkyl, halogen, —CN, or —OR 8 .
  • R 2 is oxo.
  • R 3 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, —CN, —OR, —SR 8 , —NR 9 R 10 , —C(O)NR 9 R 10 , —NR 8 C(O)R 9 , —NR 8 C(O)NR 9 R 10 , —S(O)R 8 , —S(O) 2 R 8 , —NR 8 S(O)R 9 , —NR 8 S(O) 2 R 9 , —S(O)NR 9 R 10 , —S(O) 2 NR 9 R 10 , C 3 -C 6 cycloalkyl, 3-12-membered heterocyclyl, 5- to 10-membered heteroaryl or C 6 -C 14 aryl.
  • R 3 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, —CN, —OR 8 , —SR 8 , —NR 9 R 10 , —C(O)NR 9 R 10 , —NR 8 C(O)R 9 , C 3 -C 6 cycloalkyl, 3-12-membered heterocyclyl, 5- to 10-membered heteroaryl or C 6 -C 14 aryl.
  • R 3 is C 1 -C 6 alkyl, halogen, —CN, —OR 8 , —SR 8 or —NR 9 R 10 .
  • R 3 is —CH 3 , halogen, —CN or —OCH 3 .
  • R 3 is H or methyl.
  • R 3 is H, C 1 -C 6 alkyl, halogen, —CN, or —OR 8 .
  • R 4 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, —CN, —OR, —SR 8 , —NR 9 R 10 , —C(O)NR 9 R 10 , —NR 8 C(O)R 9 , —NR 8 C(O)NR 9 R 10 , —S(O)R 8 , —S(O) 2 R, —NR 8 S(O)R 9 , —NR 8 S(O) 2 R 9 , —S(O)NR 9 R 10 , —S(O) 2 NR 9 R 10 , C 3 -C 6 cycloalkyl, 3-12-membered heterocyclyl, 5- to 10-membered heteroaryl or C 6 -C 14 aryl.
  • R 4 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, —CN, —OR 8 , —SR 8 , —NR 9 R 10 , —C(O)NR 9 R 10 , —NR 8 C(O)R 9 , C 3 -C 6 cycloalkyl, 3-12-membered heterocyclyl, 5- to 10-membered heteroaryl or C 6 -C 14 aryl.
  • R 4 is C 1 -C 6 alkyl, halogen, —CN, —OR 8 , —SR 8 or —NR 9 R 10 . In some embodiments of a compound of Formula (I), (II), or (III), R 4 is —CH 3 , halogen, —CN or —OCH 3 . In some embodiments of a compound of Formula (I), (II), or (III), R 4 is H or methyl. In some embodiments of a compound of Formula (I), (II), or (III), R 4 is H, C 1 -C 6 alkyl, halogen, —CN, or —OR 8 . In some embodiments of a compound of Formula (I), (II), or (III), R 4 is oxo.
  • R 5 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, —CN, —OR 8 , —SR 8 , —NR 9 R 10 , —C(O)NR 9 R 10 , —NR 8 C(O)R 9 , —NR 8 C(O)NR 9 R 10 , —S(O)R 8 , —S(O) 2 R 8 , —NR 8 S(O)R 9 , —NR 8 S(O) 2 R 9 , —S(O)NR 9 R 10 , —S(O) 2 NR 9 R 10 , C 3 -C 6 cycloalkyl, 3-12-membered heterocyclyl, 5- to 10-membered heteroaryl or C 6 -C 14 aryl.
  • R 5 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, —CN, —OR 8 , —SR 8 , —NR 9 R 10 , —C(O)NR 9 R 10 , —NR 8 C(O)R 9 , C 3 -C 6 cycloalkyl, 3-12-membered heterocyclyl, 5- to 10-membered heteroaryl or C 6 -C 14 aryl.
  • R 5 is C 1 -C 6 alkyl, halogen, —CN, —OR 8 , —SR 8 or —NR 9 R 10 .
  • R 5 is —CH 3 , halogen, —CN or —OCH 3 .
  • R 5 is H or methyl.
  • R 5 is H, C 1 -C 6 alkyl, halogen, —CN, or —OR 8 .
  • R 5 is H, C 1 -C 6 alkyl, halogen, —CN, or —OR 8 . In some embodiments, R 5 is H. In particular embodiments of a compound of Formula (I), (II), or (III), R 1 is H or C 1 -C 6 alkyl (such as methyl) and R 5 is H, C 1 -C 6 alkyl, halogen, —CN, or —OR 8 .
  • A is C 6 -C 12 aryl optionally further substituted with R 6 .
  • A is phenyl or naphthyl, optionally substituted with R 6 .
  • A is phenyl.
  • A is naphthyl.
  • A is phenyl or naphthyl, substituted with one or more groups selected from halogen, —CN, —OR, —SR 8 , —NR 9 R 10 , —NO 2 , —C(O)R 8 , —C(O)OR 8 , —C(O)NR 9 R 10 , —C(O)NR 8 S(O) 2 R 9 , —OC(O)R 8 , —OC(O)NR 9 R 10 , —NR 8 C(O)R 9 , —NR 8 C(O)NR 9 R 10 , —S(O)R 8 , —S(O) 2 R 8 , C 3 -C 6 cycloalkyl and C 1 -C 6 alkyl optionally substituted by halogen.
  • A is phenyl, substituted with one or more groups selected from halogen, —CN, —OH, —OC 1 -C 6 alkyl, —NH 2 , —NO 2 , C 3 -C 6 cycloalkyl and C 1 -C 6 alkyl optionally substituted by halogen.
  • A is phenyl, substituted with one or more groups selected from halogen, —OH, and C 1 -C 6 alkyl.
  • A is 5- to 10-membered heteroaryl optionally further substituted with R 6 .
  • A is selected from the group consisting of pyridyl, quinolinyl, isoquinolinyl, quinoxalinyl, cinnolinyl, quinazolinyl, naphthyridinyl, benzoxazolyl, benzothiazolyl, benzoimidazoyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, isoxazolyl, oxazolyl, oxadiazolyl, thiophenyl, isothiazolyl, thiazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, indo
  • A is a 10-membered heteroaryl optionally further substituted with R 6 , wherein the 10-membered heteroaryl is a 6/6-ring fused system (i.e., a ring system formed by fusing a 6-membered ring with a 6-membered ring).
  • A is a 9-membered heteroaryl, wherein the 9-membered heteroaryl is a 6/5-ring fused system (i.e., a ring system formed by fusing a 6-membered ring with a 5-membered ring).
  • the 6/5-ring fused system of A is attached to the rest of the compound via the 6-membered ring.
  • the 6/5-ring fused system of A is attached to the rest of the compound via the 5-membered ring.
  • A is selected from the group consisting of:
  • A is selected from the group consisting of:
  • A is 5- to 10-membered heteroaryl optionally further substituted with one or more groups selected from halogen, —CN, —OR 8 , —SR 8 , —NR 9 R 10 , —NO 2 , —C(O)R 8 , —C(O)OR 8 , —C(O)NR 9 R 10 , —C(O)NR 8 S(O) 2 R 9 , —OC(O)R 8 , —OC(O)NR 9 R 10 , —NR 8 C(O)R 9 , —NR 8 C(O)NR 9 R 10 , —S(O)R 8 , —S(O) 2 R 8 , C 3 -C 6 cycloalkyl and C 1 -C 6 alkyl
  • A is a 9- to 10-membered carbocycle optionally further substituted with R 6 .
  • A is a 10-membered carbocycle, wherein the 10-membered carbocycle is a 6/6-ring fused system (i.e., a ring system formed by fusing a 6-membered ring with a 6-membered ring).
  • A is a 9-membered carbocycle, wherein the 9-membered carbocycle is a 6/5-ring fused system (i.e., a ring system formed by fusing a 6-membered ring with a 5-membered ring).
  • the 6/5-ring fused system of A is attached to the rest of the compound via the 6-membered ring. In other embodiments, the 6/5-ring fused system of A is attached to the rest of the compound via the 5-membered ring. In some embodiments, A is a fully saturated 9- to 10-membered carbocycle. In some embodiments, A is a partially saturated 9- to 10-membered carbocycle.
  • A is selected from the group consisting of decahydronaphthalenyl, octahydroindenyl, 1,2,3,4-tetrahydronaphthalenyl, and 2,3-dihydroindenyl, each optionally substituted with R 6 .
  • A is a 9- to 10-membered carbocycle optionally further substituted with one or more groups selected from halogen, —CN, —OR 8 , —SR 8 , —NR 9 R 10 , —NO 2 , —C(O)R 8 , —C(O)OR 8 , —C(O)NR 9 R 10 , —C(O)NR 8 S(O) 2 R 9 , —OC(O)R 8 , —OC(O)NR 9 R 10 , —NR 8 C(O)R 9 , —NR 8 C(O)NR 9 R 10 , —S(O)R 8 , —S(O) 2 R 8 , C 3 -C 6 cycloalkyl and C 1 -C 6 alkyl optionally substituted by halogen.
  • A is a 9- to 10-membered carbocycle optionally further substituted with one or more groups selected from C 1 -C 6 alkyl, halogen, —CN, —OH, and —OC 1 -C 6 alkyl.
  • A is a 9- to 10-membered heterocycle optionally further substituted with R 6 .
  • A is a 10-membered heterocycle optionally further substituted with R 6 , wherein the 10-membered heterocycle is a 6/6-ring fused system (i.e., a ring system formed by fusing a 6-membered ring with a 6-membered ring).
  • A is a 9-membered heterocycle, wherein the 9-membered heterocycle is a 6/5-ring fused system (i.e., a ring system formed by fusing a 6-membered ring with a 5-membered ring).
  • the 6/5-ring fused system of A is attached to the rest of the compound via the 6-membered ring. In other embodiments, the 6/5-ring fused system of A is attached to the rest of the compound via the 5-membered ring. In some embodiments, A is a fully saturated 9- to 10-membered heterocycle. In some embodiments, A is a partially saturated 9- to 10-membered heterocycle.
  • A is selected from the group consisting of tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, indolinyl, isoindolinyl, tetrahydronaphthyridinyl and hexahydrobenzoimidazolyl, each optionally further substituted with R 6 .
  • A is a 9- to 10-membered heterocycle optionally further substituted with one or more groups selected from halogen, —CN, —OR 8 , —SR 8 , —NR 9 R 10 , —NO 2 , —C(O)R 8 , —C(O)OR 8 , —C(O)NR 9 R 10 , —C(O)NR 8 S(O) 2 R 9 , —OC(O)R 8 , —OC(O)NR 9 R 10 , —NR 8 C(O)R 9 , —NR 8 C(O)NR 9 R 10 , —S(O)R 8 , —S(O) 2 R 8 , C 3 -C 6 cycloalkyl and C 1 -C 6 alkyl optionally substituted by halogen.
  • A is a 9- to 10-membered heterocycle optionally further substituted with one or more groups selected from C 1 -C 6 alkyl, halogen, —CN, —OH, and —OC 1 -C 6 alkyl. In some embodiments, A is selected from the group consisting of
  • R 6 is independently selected from the group consisting of halogen, —CN, —OR 8 , —SR 8 , —NR 9 R 10 , —NO 2 , —C(O)R 8 , —C(O)OR 8 , —C(O)NR 9 R 10 , —C(O)NR 8 S(O) 2 R 9 , —OC(O)R 8 , —OC(O)NR 9 R 10 , —NR 8 C(O)R 9 , —NR 8 C(O)NR 9 R 10 , —S(O)R 8 , —S(O) 2 R 8 , C 3 -C 6 cycloalkyl and C 1 -C 6 alkyl optionally substituted by halogen.
  • R 6 is independently selected from the group consisting of halogen, —CN, —OR 8 , —SR 8 , —NR 9 R 10 , —NO 2 , —C(O)R 8 , —C
  • each R 6 is independently selected from the group consisting of halogen, —CN, —OR 8 , —SR 8 , —NR 9 R 10 , —NO 2 , —C(O)R 8 , —C(O)OR 8 , —C(O)NR 9 R 10 , —C(O)NR 8 S(O) 2 R 9 , —OC(O)R 8 , —OC(O)NR 9 R 10 , —NR 8 C(O)R 9 , —NR 8 C(O)NR 9 R 10 , —S(O)R 8 , —S(O) 2 R 8 , C 3 -C 6 cycloalkyl and C 1 -C 6 alkyl optionally substituted by halogen.
  • R 6 is independently selected from the group consisting of C 1 -C 6 alkyl, halogen, —CN, and —OR 8 , —NR 9 R 10 , —NO 2 , —C(O)R
  • A is selected from the group consisting of:
  • A is selected from the group consisting of:
  • A is
  • each description of A may be combined with each description of R 1 -R 5 the same as if each and every combination were specifically and individually listed. It is similarly understood that each description of A may be combined with each description of B (and further with each description of R 1 -R 5 ) the same as if each and every combination were specifically and individually listed. For example, in one aspect, it is understood that each description of A may be combined in one aspect with a variation in which R 1 , R 3 , R 5 are each hydrogen and one of R 2 and R 4 is hydrogen and one of R 2 and R 4 is oxo.
  • each description of A is combined in one aspect with a variation in which R 1 , R 2 , R 3 , R 5 are each hydrogen and R 4 is oxo.
  • each description of A is combined in one aspect with a variation in which R 1 , R 3 , R 4 , R 5 are each hydrogen and R 2 is oxo.
  • Such embodiments may further be combined with each description of B.
  • B is phenyl, optionally further substituted with R 7 .
  • B is 5- to 6-membered heteroaryl optionally further substituted with R 7 .
  • B is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, isoxazolyl, oxazolyl, oxadiazolyl, thiophenyl, isothiazolyl, thiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, or tetrazinyl, each optionally substituted with R 7 .
  • B is furanyl, pyridinyl, oxazoyl, or oxadiazoyl, each optionally substituted with R 7 .
  • B is a 5- to 6-membered carbocycle optionally further substituted with R 7 .
  • B is a fully saturated 5- to 6-membered carbocycle optionally further substituted with R 7 .
  • B is cyclopentyl or cyclohexyl, optionally further substituted with R 7 .
  • B is a 5- to 6-membered carbocycle optionally substituted with one or more groups selected from halogen, —CN, —OR 8 , —SR 8 , —NR 9 R 10 , —NO 2 , —C(O)R 8 , —C(O)OR 8 , —C(O)NR 9 R 10 , —C(O)NR 8 S(O) 2 R 9 , —OC(O)R 8 , —OC(O)NR 9 R 10 , —NR 8 C(O)R 9 , —NR 8 C(O)NR 9 R 10 , —S(O)R 8 , —S(O) 2 R 8 , C 3 -C 6 cycloalkyl and C 1 -C 6 alkyl optionally substituted by halogen.
  • B is a 5- to 6-membered carbocycle optionally substituted with halogen.
  • B is a 5- to 6-membered heterocycle optionally further substituted with R 7 .
  • B is a fully saturated 5- to 6-membered heterocycle optionally further substituted with R 7 .
  • B is pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydrothiophenyl, oxathiolanyl, sulfolanyl, piperidinyl, piperazinyl, tetrahydropyranyl, dioxanyl, thianyl, dithianyl, trithianyl, morpholinyl, thiomorpholinyl optionally further substituted with R 7 .
  • B is a 5- to 6-membered heterocycle optionally substituted with one or more groups selected from halogen, —CN, —OR 8 , —SR 8 , —NR 9 R 10 , —NO 2 , —C(O)R 8 , —C(O)OR 8 , —C(O)NR 9 R 10 , —C(O)NR 8 S(O) 2 R 9 , —OC(O)R 8 , —OC(O)NR 9 R 10 , —NR 8 C(O)R 9 , —NR 8 C(O)NR 9 R 10 , —S(O)R 8 , —S(O) 2 R 8 , C 3 -C 6 cycloalkyl and C 1 -C 6 alkyl optionally substituted by halogen.
  • B is a 5- to 6-membered heterocycle optionally substituted with halogen.
  • B is a 9- to 10-membered heteroaryl optionally further substituted with R 7 .
  • B is selected from the group consisting of pyridyl, quinolinyl, isoquinolinyl, quinoxalinyl, cinnolinyl, quinazolinyl, naphthyridinyl, benzoxazolyl, benzothiazolyl, benzoimidazoyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, isoxazolyl, oxazolyl, oxadiazolyl, thiophenyl, isothiazolyl, thiazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl,
  • B is a 9- to 10-membered heteroaryl optionally substituted with one or more groups selected from halogen, —CN, —OR 8 , —SR 8 , —NR 9 R 10 , —NO 2 , —C(O)R 8 , —C(O)OR 8 , —C(O)NR 9 R 10 , —C(O)NR 8 S(O) 2 R 9 , —OC(O)R 8 , —OC(O)NR 9 R 10 , —NR 8 C(O)R 9 , —NR 8 C(O)NR 9 R 10 , —S(O)R 8 , —S(O) 2 R 8 , C 3 -C 6 cycloalkyl and C 1 -C 6 alkyl optionally substituted by halogen.
  • halogen —CN, —OR 8 , —SR 8 , —NR 9 R 10 , —NO 2 , —C(O)R 8 ,
  • R 7 is independently selected from the group consisting of halogen, —CN, —OR 8 , —SR 8 , —NR 9 R 10 , —NO 2 , —C(O)R 8 , —C(O)OR 8 , —C(O)NR 9 R 10 , —C(O)NR 8 S(O) 2 R 9 , —OC(O)R 8 , —OC(O)NR 9 R 10 , —NR 8 C(O)R 9 , —NR 8 C(O)NR 9 R 10 , —S(O)R 8 , —S(O) 2 R 8 , C 3 -C 6 cycloalkyl and C 1 -C 6 alkyl optionally substituted by halogen.
  • R 7 is halogen.
  • B is selected from the group consisting of:
  • B is selected from the group consisting of:
  • B is selected from the group consisting of:
  • B is selected from
  • A is C 6 -C 12 aryl or 5- to 10-membered heteroaryl, each optionally further substituted with R 6 , and B is phenyl or 5- to 6-membered heteroaryl, each optionally further substituted with R 7 .
  • A is C 6 -C 12 aryl, optionally further substituted with R 6
  • B is phenyl, optionally further substituted with R 7 .
  • A is C 6 -C 12 aryl, optionally further substituted with R 6 , and B is 5- to 6-membered heteroaryl, optionally further substituted with R 7 .
  • A is 5- to 10-membered heteroaryl, optionally further substituted with R 6
  • B is phenyl, optionally further substituted with R 7
  • A is 5- to 10-membered heteroaryl, optionally further substituted with R 6
  • B is 5- to 6-membered heteroaryl, optionally further substituted with R 7 .
  • A is 9- to 10-membered carbocycle or 9- to 10-membered heterocycle, each optionally further substituted with R 6
  • B is phenyl, 5- to 6-membered heteroaryl, 5- to 6-membered carbocycle, or 5- to 6-membered heterocycle, each optionally further substituted with R 7 .
  • A is 9- to 10-membered carbocycle, optionally further substituted with R 6
  • B is phenyl, optionally further substituted with R 7 .
  • A is 9- to 10-membered carbocycle, optionally further substituted with R 6 , and B is 5- to 6-membered heteroaryl, optionally further substituted with R 7 .
  • A is 9- to 10-membered carbocycle, optionally further substituted with R 6 , and B is 5- to 6-membered carbocycle, optionally further substituted with R 7 .
  • A is 9- to 10-membered carbocycle, optionally further substituted with R 6 , and B is 5- to 6-membered heterocycle, optionally further substituted with R 7 .
  • A is C 6 -C 12 aryl or 5- to 10-membered heteroaryl, each optionally further substituted with R 6 , and B is 5- to 6-membered carbocycle or 5- to 6-membered heterocycle, each optionally further substituted with R 7 .
  • A is C 6 -C 12 aryl, optionally further substituted with R 6 , and B is 5- to 6-membered carbocycle, optionally further substituted with R 7 .
  • A is C 6 -C 12 aryl, optionally further substituted with R 6 , and B is 5- to 6-membered heterocycle, optionally further substituted with R 7 .
  • A is 5- to 10-membered heteroaryl, optionally further substituted with R 6
  • B is 5- to 6-membered carbocycle, optionally further substituted with R 7 .
  • A is 5- to 10-membered heteroaryl, optionally further substituted with R 6
  • B is 5- to 6-membered heterocycle, optionally further substituted with R 7 .
  • when A is phenyl or pyridyl, either of which is optionally further substituted with R 6 B is not a saturated heterocycle.
  • A is C 6 -C 12 aryl or 5- to 10-membered heteroaryl, each optionally further substituted with R 6 , and B is 9- to 10-membered carbocycle, optionally further substituted with R 7 .
  • A is C 6 -C 12 aryl, optionally further substituted with R 6 , and B is 9- to 10-membered carbocycle, optionally further substituted with R 7 .
  • A is 5- to 10-membered heteroaryl, optionally further substituted with R 6 , and B is 9- to 10-membered carbocycle, optionally further substituted with R 7 .
  • A is
  • R 6a , R 6b , R 6c , R 6d , R 6e , and R 6f are each independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, —CN, —OR 8 , —SR 8 , —NR 9 R 10 , —NO 2 , —C ⁇ NH(OR 8 ), —C(O)R 8 , —OC(O)R 8 , —C(O)OR 8 , —C(O)NR 9 R 10 , —OC(O)NR 9 R 10 , —NR 8 C(O)R 9 , —NR 8 C(O)OR 9 , —NR 8 C(O)NR 9 R 10 , —S(O)R 8 , —S(O) 2 R 8 , —NR 8 S(O)R 9 , —C(O)NR 8 S(O)R 9 , —
  • A is
  • R 6a , R 6b , R 6c , R 6d , R 6e , and R 6f are each independently H, C 1 -C 6 alkyl, halogen, —CN, or —OC 1 -C 6 alkyl.
  • R 6a , R 6b , R 6c , R 6d , R 6e , and R 6f are each H.
  • one of R 6a , R 6b , R 6c , R 6d , R 6e , and R 6f is Cl, F, Br, or I.
  • one of R 6a , R 6b , R 6c , R 6d , R 6e , and R 6f is Cl.
  • one of R 6a , R 6b , R 6c , R 6d , R 6e , and R 6f is halogen and the others are each H. In some embodiments, one of R 6a , R 6b , R 6c , R 6d , R 6e , and R 6f is halogen and one of R 6a , R 6b , R 6c , R 6d , R 6e , and R 6f is C 1 -C 6 alkyl.
  • R 6a , R 6b , R 6c , R 6d , R 6e , and R 6f is Cl and one of R 6a , R 6b , R 6c , R 6d , R 6e , and R 6f is methyl.
  • R 6a is C 1 -C 6 alkyl.
  • R 6b is C 1 -C 6 alkyl.
  • R 6c is C 1 -C 6 alkyl.
  • R 6d is C 1 -C 6 alkyl.
  • R 6e is C 1 -C 6 alkyl.
  • R 6f is C 1 -C 6 alkyl.
  • R 6a is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secbutyl, or tertbutyl.
  • R 6b is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secbutyl, or tertbutyl.
  • R 6c is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secbutyl, or tertbutyl.
  • R 6d is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secbutyl, or tertbutyl.
  • R 6e is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secbutyl, or tertbutyl.
  • R 6f is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secbutyl, or tertbutyl.
  • R 6a is C 1 -C 6 alkyl and R 6b is halogen. In some embodiments, R 6a is C 1 -C 6 alkyl and R 6c is halogen. In some embodiments, R 6a is C 1 -C 6 alkyl and R 6d is halogen. In some embodiments, R 6a is C 1 -C 6 alkyl and R 6e is halogen. In some embodiments, R 6a is C 1 -C 6 alkyl and R 6f is halogen. In some embodiments, R 6b is C 1 -C 6 alkyl and R 6a is halogen. In some embodiments, R 6b is C 1 -C 6 alkyl and R 6c is halogen.
  • R 6b is C 1 -C 6 alkyl and R 6d is halogen. In some embodiments, R 6b is C 1 -C 6 alkyl and R 6e is halogen. In some embodiments, R 6b is C 1 -C 6 alkyl and R 6f is halogen. In some embodiments, R 6c is C 1 -C 6 alkyl and R 6a is halogen. In some embodiments, R 6c is C 1 -C 6 alkyl and R 6b is halogen. In some embodiments, R 6c is C 1 -C 6 alkyl and R 6d is halogen. In some embodiments, R 6c is C 1 -C 6 alkyl and R 6e is halogen.
  • R 6c is C 1 -C 6 alkyl and R 6f is halogen.
  • R 6d is C 1 -C 6 alkyl and R 6a is halogen.
  • R 6d is C 1 -C 6 alkyl and R 6b is halogen.
  • R 6d is C 1 -C 6 alkyl and R 6c is halogen.
  • R 6d is C 1 -C 6 alkyl and R 6e is halogen.
  • R 6d is C 1 -C 6 alkyl and R 6f is halogen.
  • R 6e is C 1 -C 6 alkyl and R 6a is halogen.
  • R 6e is C 1 -C 6 alkyl and R 6b is halogen. In some embodiments, R 6e is C 1 -C 6 alkyl and R 6c is halogen. In some embodiments, R 6e is C 1 -C 6 alkyl and R 6d is halogen. In some embodiments, R 6e is C 1 -C 6 alkyl and R 6f is halogen. In some embodiments, R 6f is C 1 -C 6 alkyl and R 6a is halogen. In some embodiments, R 6f is C 1 -C 6 alkyl and R 6b is halogen. In some embodiments, R 6f is C 1 -C 6 alkyl and R 6c is halogen.
  • R 6f is C 1 -C 6 alkyl and R 6d is halogen. In some embodiments, R 6f is C 1 -C 6 alkyl and R 6e is halogen. In some embodiments, two of R 6a , R 6b , R 6c , R 6d , R 6e , and R 6f are halogen. In some embodiments, two of R 6a , R 6b , R 6c , R 6d , R 6e , and R 6f are C 1 -C 6 alkyl.
  • A is
  • R 6a , R 6b , R 6c , R 6d , R 6e , and R 6f are independently selected from the group consisting of C 1 -C 6 alkyl, halogen, —CN, and —OC 1 -C 6 alkyl, and the remainder of R 6a , R 6b , R 6c , R 6d , R 6e , and R 6f are each H; and B is phenyl, optionally substituted with R 7 .
  • A is
  • R 6a , R 6b , R 6c , R 6d , R 6e , and R 6f are independently selected from the group consisting of C 1 -C 6 alkyl, halogen, —CN, and —OC 1 -C 6 alkyl, and the remainder of R 6a , R 6b , R 6c , R 6d , R 6e , and R 6f are each H; and B is a 5- to 6-membered carbocycle, optionally substituted with R 7 .
  • A is
  • R 6a , R 6b , R 6c , R 6d , R 6e , and R 6f are independently selected from the group consisting of C 1 -C 6 alkyl, halogen, —CN, and —OC 1 -C 6 alkyl, and the remainder of R 6a , R 6b , R 6c , R 6d , R 6e , and R 6f are each H; and B is a 5- to 6-membered heterocycle, optionally substituted with R 7 .
  • A is
  • R 6a , R 6b , R 6c , R 6d , R 6e , and R 6f are independently selected from the group consisting of C 1 -C 6 alkyl, halogen, —CN, and —OC 1 -C 6 alkyl, and the remainder of R 6a , R 6b , R 6c , R 6d , R 6e , and R 6f are each H; and B is a 5- to 6-membered heterocycle, optionally substituted with R 7 .
  • A is
  • R 6a , R 6b , R 6c , R 6d , R 6e , and R 6f are independently selected from the group consisting of C 1 -C 6 alkyl, halogen, —CN, and —OC 1 -C 6 alkyl, and the remainder of R 6a , R 6b , R 6c , R 6d , R 6e , and R 6f are each H; and B is a 9- to 10-membered heteroaryl, optionally substituted with R 7 .
  • A is
  • R 6a , R 6b , R 6c , R 6d , R 6e , and R 6f are independently selected from the group consisting of C 1 -C 6 alkyl, halogen, —CN, and —OC 1 -C 6 alkyl, and the remainder of R 6a , R 6b , R 6c , R 6e , and R 6f are each H; and B is selected from the group consisting of:
  • A is
  • R 6a , R 6b , R 6c , R 6d , R 6e , and R 6f are independently selected from the group consisting of C 1 -C 6 alkyl, halogen, —CN, and —OC 1 -C 6 alkyl, and the remainder of R 6a , R 6b , R 6c , R 6d , R 6e , and R 6f are each H; and B is selected from the group consisting of:
  • A is
  • R 6a , R 6b , R 6c , R 6d , R 6e , and R 6f are independently selected from the group consisting of C 1 -C 6 alkyl, halogen, —CN, and —OC 1 -C 6 alkyl, and the remainder of R 6a , R 6b , R 6c , R 6d , R 6e , and R 6f are each H; and B is selected from the group consisting of
  • A is
  • R 6a , R 6b , R 6c , R 6d , R 6e , and R 6f are independently selected from the group consisting of C 1 -C 6 alkyl, halogen, —CN, and —OC 1 -C 6 alkyl, and the remainder of R 6a , R 6b , R 6c , R 6d , R 6e , and R 6f are each H; and B is selected from and
  • A is
  • R 6b , R 6e , R 6d , R 6e , R 6f , and R 6g are each independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, —CN, —OR 8 , —SR 8 , —NR 9 R 10 , —NO 2 , —C ⁇ NH(OR 8 ), —C(O)R 8 , —OC(O)R 8 , —C(O)OR 8 , —C(O)NR 9 R 10 , —OC(O)NR 9 R 10 , —NR 8 C(O)R 9 , —NR 8 C(O)OR 9 , —NR 8 C(O)NR 9 R 10 , —S(O)R 8 , —S(O) 2 R 8 , —NR 8 S(O)R 9 , —C(O)NR 8 S(O)R 9 , —
  • A is
  • R 6b , R 6c , R 6d , R 6e , R 6f , and R 6g are each independently H, C 1 -C 6 alkyl, halogen, —CN, or —OC 1 -C 6 alkyl.
  • R 6b , R 6c , R 6d , R 6e , R 6f , and R 6g are each H.
  • one of R 6b , R 6c , R 6d , R 6e , R 6f , and R 6g is Cl, F, Br, or I.
  • one of R 6b , R 6c , R 6d , R 6e , R 6f , and R 6g is Cl.
  • one of R 6b , R 6c , R 6d , R 6e , R 6f , and R 6g is halogen and the others are each H. In some embodiments, one of R 6b , R 6c , R 6d , R 6e , R 6f , and R 6g is halogen and one of R 6b , R 6c , R 6d , R 6e , R 6f , and R 6g is C 1 -C 6 alkyl.
  • one of R 6b , R 6c , R 6d , R 6e , R 6f , and R 6g is Cl and one of R 6b , R 6c , R 6d , R 6e , R 6f and R 6g is methyl.
  • R 6g is C 1 -C 6 alkyl.
  • R 6b is C 1 -C 6 alkyl.
  • R 6c is C 1 -C 6 alkyl.
  • R 6d is C 1 -C 6 alkyl.
  • R 6e is C 1 -C 6 alkyl.
  • R 6f is C 1 -C 6 alkyl.
  • R 6g is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secbutyl, or tertbutyl.
  • R 6b is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secbutyl, or tertbutyl.
  • R 6c is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secbutyl, or tertbutyl.
  • R 6d is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secbutyl, or tertbutyl.
  • R 6e is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secbutyl, or tertbutyl.
  • R 6f is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secbutyl, or tertbutyl.
  • R 6g is C 1 -C 6 alkyl and R 6b is halogen. In some embodiments, R 6g is C 1 -C 6 alkyl and R 6c is halogen. In some embodiments, R 6g is C 1 -C 6 alkyl and R 6d is halogen. In some embodiments, R 6g is C 1 -C 6 alkyl and R 6e is halogen. In some embodiments, R 6g is C 1 -C 6 alkyl and R 6f is halogen. In some embodiments, R 6b is C 1 -C 6 alkyl and R 6g is halogen. In some embodiments, R 6b is C 1 -C 6 alkyl and R 6c is halogen.
  • R 6b is C 1 -C 6 alkyl and R 6d is halogen. In some embodiments, R 6b is C 1 -C 6 alkyl and R 6e is halogen. In some embodiments, R 6b is C 1 -C 6 alkyl and R 6f is halogen. In some embodiments, R 6c is C 1 -C 6 alkyl and R 6g is halogen. In some embodiments, R 6c is C 1 -C 6 alkyl and R 6b is halogen. In some embodiments, R 6c is C 1 -C 6 alkyl and R 6d is halogen. In some embodiments, R 6c is C 1 -C 6 alkyl and R 6e is halogen.
  • R 6c is C 1 -C 6 alkyl and R 6f is halogen.
  • R 6d is C 1 -C 6 alkyl and R 6g is halogen.
  • R 6d is C 1 -C 6 alkyl and R 6b is halogen.
  • R 6d is C 1 -C 6 alkyl and R 6c is halogen.
  • R 6d is C 1 -C 6 alkyl and R 6e is halogen.
  • R 6d is C 1 -C 6 alkyl and R 6f is halogen.
  • R 6e is C 1 -C 6 alkyl and R 6g is halogen.
  • R 6e is C 1 -C 6 alkyl and R 6b is halogen. In some embodiments, R 6e is C 1 -C 6 alkyl and R 6c is halogen. In some embodiments, R 6e is C 1 -C 6 alkyl and R 6d is halogen. In some embodiments, R 6e is C 1 -C 6 alkyl and R 6f is halogen. In some embodiments, R 6f is C 1 -C 6 alkyl and R 6g is halogen. In some embodiments, R 6f is C 1 -C 6 alkyl and R 6b is halogen. In some embodiments, R 6f is C 1 -C 6 alkyl and R 6c is halogen.
  • R 6f is C 1 -C 6 alkyl and R 6d is halogen. In some embodiments, R 6f is C 1 -C 6 alkyl and R 6e is halogen. In some embodiments, two of R 6b , R 6c , R 6d , R 6e , R 6f , and R 6g are halogen. In some embodiments, two of R 6b , R 6c , R 6d , R 6e , R 6f , and R 6g are C 1 -C 6 alkyl.
  • A is
  • R 6b , R 6c , R 6d , R 6e , R 6f , and R 6g are independently selected from the group consisting of C 1 -C 6 alkyl, halogen, —CN, and —OC 1 -C 6 alkyl, and the remainder of R 6b , R 6c , R 6d , R 6e , R 6f , and R 6g are each H; and B is phenyl, optionally substituted with R 7 .
  • A is
  • R 6b , R 6c , R 6d , R 6e , R 6f , and R 6g are independently selected from the group consisting of C 1 -C 6 alkyl, halogen, —CN, and —OC 1 -C 6 alkyl, and the remainder of R 6b , R 6c , R 6d , R 6e , R 6f , and R 6g are each H; and B is a 5- to 6-membered heteroaryl, optionally substituted with R 7 .
  • A is
  • R 6b , R 6c , R 6d , R 6e , R 6f , and R 6g are independently selected from the group consisting of C 1 -C 6 alkyl, halogen, —CN, and —OC 1 -C 6 alkyl, and the remainder of R 6b , R 6c , R 6d , R 6e , R 6f , and R 6g are each H; and B is a 5- to 6-membered carbocycle, optionally substituted with R 7 .
  • A is
  • R 6b , R 6c , R 6d , R 6e , R 6f , and R 6g are independently selected from the group consisting of C 1 -C 6 alkyl, halogen, —CN, and —OC 1 -C 6 alkyl, and the remainder of R 6b , R 6c , R 6d , R 6e , R 6f , and R 6g are each H; and B is a 5- to 6-membered heterocycle, optionally substituted with R 7 .
  • A is
  • R 6b , R 6c , R 6d , R 6e , R 6f , and R 6g are independently selected from the group consisting of C 1 -C 6 alkyl, halogen, —CN, and —OC 1 -C 6 alkyl, and the remainder of R 6b , R 6c , R 6d , R 6e , R 6f , and R 6g are each H; and B is a 9- to 10-membered heteroaryl, optionally substituted with R 7 .
  • A is
  • R 6b , R 6c , R 6d , R 6e , R 6f , and R 6g are independently selected from the group consisting of C 1 -C 6 alkyl, halogen, —CN, and —OC 1 -C 6 alkyl, and the remainder of R 6b , R 6c , R 6d , R 6e , R 6f , and R 6g are each H; and B is selected from the group consisting of:
  • A is
  • R 6b , R 6c , R 6d , R 6e , R 6f , and R 6g are independently selected from the group consisting of C 1 -C 6 alkyl, halogen, —CN, and —OC 1 -C 6 alkyl, and the remainder of R 6b , R 6c , R 6d , R 6e , R 6f , and R 6g are each H; and B is selected from the group consisting of:
  • A is
  • X 1 is selected from the group consisting of N, C, and CH;
  • X 2 is selected from the group consisting of NH, O, and S;
  • R 6a , R 6b , and R 6c are each independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, —CN, —OR 8 , —SR 8 , —NR 9 R 10 , —NO 2 , —C ⁇ NH(OR 8 ), —C(O)R 8 , —OC(O)R 8 , —C(O)OR 8 , —C(O)NR 9 R 10 , —OC(O)NR 9 R 10 , —NR 8 C(O)R 9 , —NR 8 C(O)OR 9 , —NR 8 C(O)NR 9 R 10 , —S(O)R 8 , —S(O) 2 R 8 , —NR 8
  • A is
  • R 6a , R 6b , and R 6c are each H. In some embodiments, one of R 6a , R 6b , and R 6c is Cl, F, Br, or I. In some embodiments, one of R 6a , R 6b , and R 6c is Cl. In some embodiments, one of R 6a , R 6b , and R 6c is halogen and the others are each H. In some embodiments, one of R 6a , R 6b , and R 6c is halogen and one of R 6a , R 6b , and R 6c is C 1 -C 6 alkyl.
  • R 6a , R 6b , and R 6c are independently selected from the group consisting of C 1 -C 6 alkyl, halogen, —CN, and —OC 1 -C 6 alkyl, and the remainder of R 6a , R 6b , and R 6c are each H; and B is phenyl, optionally substituted with R 7 .
  • R 6a , R 6b , and R 6c are independently selected from the group consisting of C 1 -C 6 alkyl, halogen, —CN, and —OC 1 -C 6 alkyl, and the remainder of R 6a , R 6b , and R 6c are each H; and B is a 5- to 6-membered heteroaryl, optionally substituted with R 7 .
  • A is
  • R 6a , R 6b , and R 6c are independently selected from the group consisting of C 1 -C 6 alkyl, halogen, —CN, and —OC 1 -C 6 alkyl, and the remainder of R 6a , R 6b , and R 6c are each H; and B is a 5- to 6-membered heterocycle, optionally substituted with R 7 .
  • R 6a , R 6b , and R 6c are independently selected from the group consisting of C 1 -C 6 alkyl, halogen, —CN, and —OC 1 -C 6 alkyl, and the remainder of R 6a , R 6b , and R 6c are each H; and B is a 9- to 10-membered heteroaryl, optionally substituted with R 7 .
  • R 6a , R 6b , and R 6c are independently selected from the group consisting of C 1 -C 6 alkyl, halogen, —CN, and —OC 1 -C 6 alkyl, and the remainder of R 6a , R 6b , and R 6c are each H; and B is selected from the group consisting of:
  • A is
  • A is
  • X 1 is selected from the group consisting of N, C, and CH;
  • X 2 is selected from the group consisting of NH, O, and S;
  • R 6g , R 6b , and R 6c are each independently H, C 1 -C 6 alkyl, halogen, —CN, or —OC 1 -C 6 alkyl.
  • A is
  • R 6g , R 6b , and R 6c are each H. In some embodiments, one of R 6g , R 6b , and R 6c is Cl, F, Br, or I. In some embodiments, one of R 6g , R 6b , and R 6c is Cl. In some embodiments, one of R 6g , R 6b , and R 6c is halogen and the others are each H. In some embodiments, one of R 6g , R 6b , and R 6c is halogen and one of R 6g , R 6b , and R 6c is C 1 -C 6 alkyl.
  • R 6b is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secbutyl, or tertbutyl.
  • R 6c is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secbutyl, or tertbutyl.
  • R 6g is C 1 -C 6 alkyl and R 6b is halogen. In some embodiments, R 6g is C 1 -C 6 alkyl and R 6c is halogen.
  • R 6b is C 1 -C 6 alkyl and R 6g is halogen. In some embodiments, R 6b is C 1 -C 6 alkyl and R 6c is halogen. In some embodiments, R 6c is C 1 -C 6 alkyl and R 6g is halogen. In some embodiments, R 6c is C 1 -C 6 alkyl and R 6b is halogen. In some embodiments, two of R 6g , R 6b , and R 6c are halogen. In some embodiments, two of R 6g , R 6b , and R 6c are C 1 -C 6 alkyl.
  • A is
  • R 6b , and R 6c are independently selected from the group consisting of C 1 -C 6 alkyl, halogen, —CN, and —OC 1 -C 6 alkyl, and the remainder of R 6g , R 6b , and R 6c are each H; and B is phenyl, optionally substituted with R 7 .
  • R 6g , R 6b , and R 6c are independently selected from the group consisting of C 1 -C 6 alkyl, halogen, —CN, and —OC 1 -C 6 alkyl, and the remainder of R 6g , R 6b , and R 6c are each H; and B is a 5- to 6-membered carbocycle, optionally substituted with R 7 .
  • A is
  • A is
  • R 6g , R 6b , and R 6c are independently selected from the group consisting of C 1 -C 6 alkyl, halogen, —CN, and —OC 1 -C 6 alkyl, and the remainder of R 6g , R 6b , and R 6c are each H; and B is a 9- to 10-membered heteroaryl, optionally substituted with R 7 .
  • R 6g , R 6b , and R 6c are independently selected from the group consisting of C 1 -C 6 alkyl, halogen, —CN, and —OC 1 -C 6 alkyl, and the remainder of R 6g , R 6b , and R 6c are each H; and B is a 9- to 10-membered heteroaryl, optionally substituted with R 7 .
  • A is
  • A is
  • R 6g , R 6b , and R 6c are independently selected from the group consisting of C 1 -C 6 alkyl, halogen, —CN, and —OC 1 -C 6 alkyl, and the remainder of R 6g , R 6b , and R 6c are each H; and B is selected from the group consisting of:
  • R 6g , R 6b , and R 6c are independently selected from the group consisting of C 1 -C 6 alkyl, halogen, —CN, and —OC 1 -C 6 alkyl, and the remainder of R 6g , R 6b , and R 6c are each H; and B is selected from
  • salts of compounds referred to herein such as pharmaceutically acceptable salts.
  • the invention also includes any or all of the stereochemical forms, including any enantiomeric or diastereomeric forms, and any tautomers or other forms of the compounds described.
  • compositions comprising a compound as detailed herein are provided, such as compositions of substantially pure compounds.
  • a composition containing a compound as detailed herein or a salt thereof is in substantially pure form.
  • substantially pure intends a composition that contains no more than 35% impurity, wherein the impurity denotes a compound other than the compound comprising the majority of the composition or a salt thereof.
  • a composition of substantially pure compound or a salt thereof is provided wherein the composition contains no more than 25%, 20%, 15%, 10%, or 5% impurity.
  • a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 3%, 2%, 1% or 0.5% impurity.
  • the present disclosure also includes any or all of the stereochemical forms, including any enantiomeric or diastereomeric forms of the compounds described.
  • the structure or name is intended to embrace all possible isomers of a compound depicted.
  • compositions comprising a compound of the invention are also intended, such as a composition of substantially pure compound, including a specific stereochemical form thereof, or a composition comprising mixtures of compounds of the invention in any ratio, including two or more stereochemical forms, such as in a racemic or non-racemic mixture.
  • the invention also intends isotopically-labeled and/or isotopically-enriched forms of compounds described herein.
  • the compounds herein may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the compound is isotopically-labeled, such as an isotopically-labeled compound of the formula (I) or variations thereof described herein, where a fraction of one or more atoms are replaced by an isotope of the same element.
  • Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C 13 N, 15 O, 17 O, 32 P, 35 S, 18 F, 36 Cl.
  • Certain isotope labeled compounds e.g. 3 H and 14 C
  • Incorporation of heavier isotopes such as deuterium ( 2 H) can afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life, or reduced dosage requirements and, hence may be preferred in some instances.
  • Isotopically-labeled compounds of the present invention can generally be prepared by standard methods and techniques known to those skilled in the art or by procedures similar to those described in the accompanying Examples substituting appropriate isotopically-labeled reagents in place of the corresponding non-labeled reagent.
  • the invention also includes any or all metabolites of any of the compounds described.
  • the metabolites may include any chemical species generated by a biotransformation of any of the compounds described, such as intermediates and products of metabolism of the compound, such as would be generated in vivo following administration to a human.
  • the compounds detailed herein are orally bioavailable.
  • the compounds may also be formulated for parenteral (e.g., intravenous) administration.
  • One or several compounds described herein can be used in the preparation of a medicament by combining the compound or compounds as an active ingredient with a pharmacologically acceptable carrier, which are known in the art.
  • a pharmacologically acceptable carrier which are known in the art.
  • the carrier may be in various forms.
  • the manufacture of a medicament is for use in any of the methods disclosed herein, e.g., for the treatment of cancer.
  • the compounds of the invention may be prepared by a number of processes as generally described below and more specifically in the Examples hereinafter (such as the schemes provided in the Examples below).
  • the symbols when used in the formulae depicted are to be understood to represent those groups described above in relation to the formulae herein.
  • enantiomer of a compound may be accomplished from a corresponding mixture of enantiomers using any suitable conventional procedure for separating or resolving enantiomers.
  • diastereomeric derivatives may be produced by reaction of a mixture of enantiomers, e.g., a racemate, and an appropriate chiral compound. The diastereomers may then be separated by any convenient means, for example by crystallization and the desired enantiomer recovered. In another resolution process, a racemate may be separated using chiral High Performance Liquid Chromatography. Alternatively, if desired a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described.
  • Chromatography, recrystallization and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular isomer of a compound or to otherwise purify a product of a reaction.
  • Solvates and/or polymorphs of a compound provided herein or a pharmaceutically acceptable salt thereof are also contemplated.
  • Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and are often formed during the process of crystallization. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol.
  • Polymorphs include the different crystal packing arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and/or solubility. Various factors such as the recrystallization solvent, rate of crystallization, and storage temperature may cause a single crystal form to dominate
  • compounds of the formula (I) may be synthesized according to Scheme 1, 2, 3, 4, or 5.
  • a B and R 3 are as defined for formula (I), or any variation thereof detailed herein. It is understood that modifications of Scheme 3 can be made, such as further substitution of the structures depicted. Particular examples are provided in the Example section below.
  • compositions of any of the compounds detailed herein are embraced by this disclosure.
  • the present disclosure includes pharmaceutical compositions comprising a compound as detailed herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.
  • the pharmaceutically acceptable salt is an acid addition salt, such as a salt formed with an inorganic or organic acid.
  • Pharmaceutical compositions may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration or a form suitable for administration by inhalation.
  • compositions comprising a compound in purified forms are detailed herein.
  • Compositions comprising a compound as detailed herein or a salt thereof are provided, such as compositions of substantially pure compounds.
  • a composition containing a compound as detailed herein or a salt thereof is in substantially pure form.
  • the compounds herein are synthetic compounds prepared for administration to an individual.
  • compositions are provided containing a compound in substantially pure form.
  • the present disclosure embraces pharmaceutical compositions comprising a compound detailed herein and a pharmaceutically acceptable carrier.
  • methods of administering a compound are provided. The purified forms, pharmaceutical compositions and methods of administering the compounds are suitable for any compound or form thereof detailed herein.
  • a compound detailed herein or salt thereof may be formulated for any available delivery route, including an oral, mucosal (e.g., nasal, sublingual, vaginal, buccal or rectal), parenteral (e.g., intramuscular, subcutaneous or intravenous), topical or transdermal delivery form.
  • oral, mucosal e.g., nasal, sublingual, vaginal, buccal or rectal
  • parenteral e.g., intramuscular, subcutaneous or intravenous
  • topical or transdermal delivery form e.g., topical or transdermal delivery form.
  • a compound or salt thereof may be formulated with suitable carriers to provide delivery forms that include, but are not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, cataplasms (poultices), pastes, powders, dressings, creams, solutions, patches, aerosols (e.g., nasal spray or inhalers), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions or water-in-oil liquid emulsions), solutions and elixirs.
  • suitable carriers include, but are not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, cataplasms (poultic
  • One or several compounds described herein or a salt thereof can be used in the preparation of a formulation, such as a pharmaceutical formulation, by combining the compound or compounds, or a salt thereof, as an active ingredient with a pharmaceutically acceptable carrier, such as those mentioned above.
  • a pharmaceutically acceptable carrier such as those mentioned above.
  • the carrier may be in various forms.
  • pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants.
  • Formulations comprising the compound may also contain other substances which have valuable therapeutic properties.
  • Pharmaceutical formulations may be prepared by known pharmaceutical methods. Suitable formulations can be found, e.g., in Remington's Pharmaceutical Sciences , Mack Publishing Company, Philadelphia, Pa., 20 th ed. (2000), which is incorporated herein by reference.
  • Compounds as described herein may be administered to individuals in a form of generally accepted oral compositions, such as tablets, coated tablets, and gel capsules in a hard or in soft shell, emulsions or suspensions.
  • carriers which may be used for the preparation of such compositions, are lactose, corn starch or its derivatives, talc, stearate or its salts, etc.
  • Acceptable carriers for gel capsules with soft shell are, for instance, plant oils, wax, fats, semisolid and liquid poly-ols, and so on.
  • pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants.
  • any of the compounds described herein can be formulated in a tablet in any dosage form described, for example, a compound as described herein or a pharmaceutically acceptable salt thereof can be formulated as a 10 mg tablet.
  • compositions comprising a compound provided herein are also described.
  • the composition comprises a compound or salt thereof and a pharmaceutically acceptable carrier or excipient.
  • a composition of substantially pure compound is provided.
  • Compounds and compositions detailed herein such as a pharmaceutical composition containing a compound of any formula provided herein or a salt thereof and a pharmaceutically acceptable carrier or excipient, may be used in methods of administration and treatment as provided herein.
  • the compounds and compositions may also be used in in vitro methods, such as in vitro methods of administering a compound or composition to cells for screening purposes and/or for conducting quality control assays.
  • a method of treating a disease in an individual comprising administering an effective amount of a compound of formula (I) or any embodiment, variation or aspect thereof (collectively, a compound of formula (I) or the present compounds or the compounds detailed or described herein) or a pharmaceutically acceptable salt thereof, to the individual.
  • a method of treating a disease mediated by a G protein coupled receptor signaling pathway in an individual comprising administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, to the individual.
  • the disease is mediated by a class A G protein coupled receptor.
  • the disease is mediated by a class B G protein coupled receptor.
  • the disease is mediated by a class C G protein coupled receptor.
  • the G protein coupled receptor is a purinergic G protein receptor.
  • the G protein coupled receptor is an adenosine receptor, such as any of the A 1 , A 2A , A 2B , and A 3 receptors.
  • the present compositions may be used to treat a proliferative disease, such as cancer.
  • the cancer is a solid tumor.
  • the cancer is any of adult and pediatric oncology, myxoid and round cell carcinoma, locally advanced tumors, metastatic cancer, human soft tissue sarcomas, including Ewing's sarcoma, cancer metastases, including lymphatic metastases, squamous cell carcinoma, particularly of the head and neck, esophageal squamous cell carcinoma, oral carcinoma, blood cell malignancies, including multiple myeloma, leukemias, including acute lymphocytic leukemia, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, and hairy cell leukemia, effusion lymphomas (body cavity based lymphomas), thymic lymphoma
  • the present compounds or salts thereof are used in treatment of tumors which produce high levels of ATP and/or adenosine.
  • the extracellular concentration of adenosine is 10-20 times higher in the tumor compared to adjacent tissue.
  • the present compounds or salts thereof are used in treatment of tumors that express high levels of an ectonucleotidase.
  • the ectonucleotidase is CD39.
  • the ectonucleotidase is CD73.
  • Also provided herein is a method of enhancing an immune response in an individual in need thereof comprising administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, to the individual.
  • Adenosine receptors are known to play an immunosuppressive role in cancer biology. High levels of adenosine present in the tumor microenvironment bind to adenosine receptors on immune cells to provide an immunosuppressive microenvironment. Specifically, binding of adenosine to the A 2A receptor provides an immunosuppressive signal that inhibits T cell proliferation, cytokine production and cytotoxicity.
  • the immune response is enhanced by a compound of formula (I) or a salt thereof enhancing activity of natural killer (NK) cells.
  • the present compounds or salts thereof increase NK cell-meditated cytotoxicity.
  • the immune response is enhanced by enhancing the activity of CD8 + T cells.
  • the present compounds or salts thereof cause an inflammatory response in the tumor microenvironment.
  • the present disclosure further provides a method of increasing the activity of a natural killer cell in an individual comprising administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, to the individual.
  • the present compounds or salts thereof increase NK cell-meditated cytotoxicity.
  • a compound of formula (I) or a salt thereof increases the number of NK cells.
  • a compound of formula (I) or a salt thereof may be useful for modulating the activity of G protein receptor coupled signaling pathway proteins.
  • a compound of formula (I) or a salt thereof activates a G protein receptor coupled signaling pathway protein (i.e. is an agonist of a G protein receptor).
  • a compound of formula (I) or a salt thereof inhibits a G protein receptor coupled signaling pathway protein (i.e., is a G protein receptor antagonist).
  • a compound of formula (I) or a salt thereof is an adenosine receptor antagonist.
  • a compound of formula (I) or a salt thereof is an antagonist of any of the A 1 , A 2A , A 2B , and A 3 receptors.
  • a method of modulating the activity of an A 2A receptor in an individual comprising administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof to an individual.
  • a compound of formula (I) or a salt thereof is an A 2A receptor antagonist.
  • a compound of formula (I) or a salt thereof reduces A 2A receptor signaling by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%.
  • a compound of formula (I) or a salt thereof reduces A 2A receptor signaling by 40-99%, 50-99%, 60-99%, 70-99%, 80-99%, 90-99%, or 95-99%.
  • a compound of formula (I) or a salt thereof binds to the A 2A receptor with an IC 50 of less than 1 ⁇ M, less than 900 nM, less than 800 nM, less than 700 nM, less than 600 nM, less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, less than 10 nM, less than 1 nM or less than 100 pM.
  • Also provided herein is a method of modulating the activity of an A 2B receptor in an individual comprising administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof to an individual.
  • a compound of formula (I) or a salt thereof is an A 2B receptor antagonist.
  • a compound of formula (I) or a salt thereof reduces A 2B receptor signaling by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%.
  • a compound of formula (I) or a salt thereof reduces A 2B receptor signaling by 40-99%, 50-99%, 60-99%, 70-99%, 80-99%, 90-99%, or 95-99%.
  • a compound of formula (I) or a salt thereof binds to the A 2B receptor with an IC 50 of less than 1 ⁇ M, less than 900 nM, less than 800 nM, less than 700 nM, less than 600 nM, less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, less than 10 nM, less than 1 nM or less than 100 pM.
  • a compound of formula (I) or a salt thereof binds to the A 2B receptor with an IC 50 of 500 nM to 100 pM, 400 nM to 100 pM, 300 nM to 100 pM, 200 nM to 100 pM, or 100 nM to 100 pM.
  • Also provided herein is a method of modulating the activity of an A 3 receptor in an individual comprising administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof to an individual.
  • a compound of formula (I) or a salt thereof is an A 3 receptor antagonist.
  • a compound of formula (I) or a salt thereof reduces A 3 receptor signaling by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%.
  • a compound of formula (I) or a salt thereof reduces A 3 receptor signaling by 40-99%, 50-99%, 60-99%, 70-99%, 80-99%, 90-99%, or 95-99%.
  • a compound of formula (I) or a salt thereof binds to the A 3 receptor with an IC 50 of less than 1 ⁇ M, less than 900 nM, less than 800 nM, less than 700 nM, less than 600 nM, less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, less than 10 nM, less than 1 nM or less than 100 pM.
  • a compound of formula (I) or a salt thereof binds to the A 3 receptor with an IC 50 of 500 nM to 100 pM, 400 nM to 100 pM, 300 nM to 100 pM, 200 nM to 100 pM, or 100 nM to 100 pM.
  • the present invention comprises a method of inhibiting tumor metastasis in an individual in need thereof comprising administering a compound of formula (I), or a pharmaceutically acceptable salt thereof, to the individual.
  • the metastasis is to the lung, liver, lymph node, bone, adrenal gland, brain, peritoneum, muscle, or vagina.
  • a compound of formula (I) or a salt thereof inhibits metastasis of melanoma cells.
  • the present disclosure includes a method of delaying tumor metastasis comprising administering a compound of formula (I), or a pharmaceutically acceptable salt thereof, to the individual.
  • the time to metastatic is delayed by 1 month, 2 months 3 months, 4 months, 5 months, 6 months, 12 months, or more, upon treatment with the compounds of the present invention.
  • a compound of formula (I) or a salt thereof is used to treat an individual having a proliferative disease, such as cancer as described herein.
  • the individual is at risk of developing a proliferative disease, such as cancer.
  • the individual is determined to be at risk of developing cancer based upon one or more risk factors.
  • the risk factor is a family history and/or gene associated with cancer.
  • the individual has a cancer that expresses a high level of a nucleotide metabolizing enzyme.
  • an anti-PD-1 antibody and a compound of formula (I) or a salt thereof can be administered sequentially, such as anti-PD-1 antibody being administered first and a compound of formula (I) or a salt thereof second, or a compound of formula (I) or a salt thereof being administered first and anti-PD-1 antibody second.
  • an anti-PD-L1 antibody and a compound of formula (I) or a salt thereof can be administered sequentially, such as anti-PD-L1 antibody being administered first and a compound of formula (I) or a salt thereof second, or a compound of formula (I) or a salt thereof being administered first and anti-PD-L1 antibody second.
  • sequential administration can be reversed or kept in the same order at each time point of administration, sequential administrations can be combined with concurrent administrations, or any combination thereof.
  • the combination of a compound of formula (I) or a salt thereof can be further combined with an immunogenic agent, such as cancerous cells, purified tumor antigens (including recombinant proteins, peptides, and carbohydrate molecules), cells, and cells transfected with genes encoding immune stimulating cytokines.
  • an immunogenic agent such as cancerous cells, purified tumor antigens (including recombinant proteins, peptides, and carbohydrate molecules), cells, and cells transfected with genes encoding immune stimulating cytokines.
  • a compound of formula (I) or a salt thereof can be used in conjunction with anti-neoplastic antibodies.
  • treatment with an anti-cancer antibody or an anti-cancer antibody conjugated to a toxin can lead to cancer cell death (e.g., tumor cells) which would potentiate an immune response mediated by CTLA-4, PD-1, PD-L1 or a compound of formula (I) or a salt thereof.
  • a treatment of a hyperproliferative disease can include an anti-cancer antibody in combination with a compound of formula (I) or a salt thereof and anti-CTLA-4 and/or anti-PD-1 and/or anti-PD-L1 antibodies, concurrently or sequentially or any combination thereof, which can potentiate anti-tumor immune responses by the host.
  • Other antibodies that can be used to activate host immune responsiveness can be further used in combination with a compound of formula (I) or a salt thereof.
  • a compound of formula (I) or a salt thereof can be combined with an anti-CD73 therapy, such as an anti-CD73 antibody.
  • a compound of formula (I) or a salt thereof can be combined with an anti-CD39 therapy, such as an anti-CD39 antibody.
  • a compound of formula (I) or a salt thereof is administered in combination another G protein receptor antagonist, such as an adenosine A 1 and/or A 3 antagonist.
  • the dose of a compound administered to an individual may vary with the particular compound or salt thereof, the method of administration, and the particular disease, such as type and stage of cancer, being treated.
  • the amount of the compound or salt thereof is a therapeutically effective amount.
  • the effective amount of the compound may in one aspect be a dose of between about 0.01 and about 100 mg/kg.
  • Effective amounts or doses of the compounds of the invention may be ascertained by routine methods, such as modeling, dose escalation, or clinical trials, taking into account routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the disease to be treated, the subject's health status, condition, and weight.
  • An exemplary dose is in the range of about from about 0.7 mg to 7 g daily, or about 7 mg to 350 mg daily, or about 350 mg to 1.75 g daily, or about 1.75 to 7 g daily.
  • Any of the methods provided herein may in one aspect comprise administering to an individual a pharmaceutical composition that contains an effective amount of a compound provided herein or a salt thereof and a pharmaceutically acceptable excipient.
  • a compound or composition of the invention may be administered to an individual in accordance with an effective dosing regimen for a desired period of time or duration, such as at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer, which in some variations may be for the duration of the individual's life.
  • the compound is administered on a daily or intermittent schedule.
  • the compound can be administered to an individual continuously (for example, at least once daily) over a period of time.
  • the dosing frequency can also be less than once daily, e.g., about a once weekly dosing.
  • the dosing frequency can be more than once daily, e.g., twice or three times daily.
  • the dosing frequency can also be intermittent, including a ‘drug holiday’ (e.g., once daily dosing for 7 days followed by no doses for 7 days, repeated for any 14 day time period, such as about 2 months, about 4 months, about 6 months or more). Any of the dosing frequencies can employ any of the compounds described herein together with any of the dosages described herein.
  • a drug holiday e.g., once daily dosing for 7 days followed by no doses for 7 days, repeated for any 14 day time period, such as about 2 months, about 4 months, about 6 months or more.
  • the compounds provided herein or a salt thereof may be administered to an individual via various routes, including, e.g., intravenous, intramuscular, subcutaneous, oral and transdermal.
  • a compound provided herein can be administered frequently at low doses, known as ‘metronomic therapy,’ or as part of a maintenance therapy using compound alone or in combination with one or more additional drugs.
  • Metronomic therapy or maintenance therapy can comprise administration of a compound provided herein in cycles.
  • Metronomic therapy or maintenance therapy can comprise intra-tumoral administration of a compound provided herein.
  • the invention provides a method of treating cancer in an individual by parenterally administering to the individual (e.g., a human) an effective amount of a compound or salt thereof.
  • the route of administration is intravenous, intra-arterial, intramuscular, or subcutaneous.
  • the route of administration is oral.
  • the route of administration is transdermal.
  • compositions including pharmaceutical compositions as described herein for the use in treating, preventing, and/or delaying the onset and/or development of cancer and other methods described herein.
  • the composition comprises a pharmaceutical formulation which is present in a unit dosage form.
  • articles of manufacture comprising a compound of the disclosure or a salt thereof, composition, and unit dosages described herein in suitable packaging for use in the methods described herein.
  • suitable packaging is known in the art and includes, for example, vials, vessels, ampules, bottles, jars, flexible packaging and the like.
  • An article of manufacture may further be sterilized and/or sealed.
  • Kits generally comprise suitable packaging.
  • the kits may comprise one or more containers comprising any compound described herein.
  • Each component if there is more than one component
  • kits may be in unit dosage forms, bulk packages (e.g., multi-dose packages) or sub-unit doses.
  • kits may be provided that contain sufficient dosages of a compound as disclosed herein and/or a second pharmaceutically active compound useful for a disease detailed herein (e.g., hypertension) to provide effective treatment of an individual for an extended period, such as any of a week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more.
  • Kits may also include multiple unit doses of the compounds and instructions for use and be packaged in quantities sufficient for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies).
  • kits may optionally include a set of instructions, generally written instructions, although electronic storage media (e.g., magnetic diskette or optical disk) containing instructions are also acceptable, relating to the use of component(s) of the methods of the present invention.
  • the instructions included with the kit generally include information as to the components and their administration to an individual.
  • Step 6 Synthesis of ethyl (E)-3-(2-amino-5-bromo-6-phenylpyridin-3-yl)acrylate
  • Step 8 Synthesis of 6-(3-chloro-4-hydroxyphenyl)-7-phenyl-1,8-naphthyridin-2(1H)-one
  • the reaction mixture was diluted with water (30 mL) and extracted using ethyl acetate (2 ⁇ 50 mL). The separated organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by reverse phase column chromatography to afford the desired product as a TFA salt (8 mg, 11%).
  • reaction mixture was heated at 90° C. for 18 h.
  • the reaction mixture was allowed to cool to RT and extracted using ethyl acetate (2 ⁇ 35 mL).
  • the combined organic layers were washed (brine), dried (anhydrous Na 2 SO 4 ) and concentrated under vacuum to get the solid residue which was purified by reversed phase column chromatography to get the desired product as off white solid (0.006 g, 4%).
  • reaction mixture was heated at 90° C. for 16 h.
  • the reaction mixture was allowed to cool to RT and extracted using ethyl acetate (2 ⁇ 35 mL).
  • the combined organic layers were washed (brine), dried (anhydrous Na 2 SO 4 ) and concentrated under vacuum to get the solid residue which was purified by reversed phase column chromatography to get the desired product as off white solid (0.010 g, 10%).
  • Step 1 Synthesis of 3-(dimethylamino)-1-(furan-2-yl)prop-2-en-1-one
  • Step 5 Synthesis of 1-(2-amino-5-bromo-6-(furan-2-yl)pyridin-3-yl)-3-(dimethylamino)prop-2-en-1-one
  • Step 7 Synthesis of 7-(furan-2-yl)-6-(quinolin-6-yl)-1,8-naphthyridin-4(1H)-one
  • reaction was then heated at 100° C. for 16 h.
  • the reaction was allowed to cool to RT and extracted using ethyl acetate (2 ⁇ 30 mL).
  • ethyl acetate 2 ⁇ 30 mL.
  • the combined organic layers were washed (brine), dried (anhydrous Na 2 SO 4 ) and concentrated under vacuum to get the solid which was purified by supercritical fluid chromatography to get the desired product (0.018 g, 15%).
  • the reaction mixture was diluted with water (20 mL) and extracted using ethyl acetate (2 ⁇ 20 mL). The separated organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by reverse phase column chromatography to afford the desired product (15 mg, 13%).
  • the reaction mixture was diluted with water (20 mL) and extracted using ethyl acetate (2 ⁇ 20 mL). The separated organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by reverse phase column chromatography to afford the desired product (12 mg, 9%).
  • Step 1 Synthesis of (E)-3-(dimethylamino)-1-(pyridin-4-yl)prop-2-en-1-one
  • Step 4 Synthesis of 1-(6-amino-3-bromo-[2,4′-bipyridin]-5-yl)ethan-1-one
  • Step 6 Synthesis of 7-(pyridin-4-yl)-6-(quinolin-6-yl)-1,8-naphthyridin-4(1H)-one
  • Step 1 1-(3-amino-5-phenyl-6-(quinolin-6-yl)pyrazin-2-yl)ethan-1-one
  • reaction was monitored by LCMS and found to be complete after 12 h.
  • the reaction mixture was cooled to RT, diluted with water (20 mL) and extracted with ethyl acetate (2 ⁇ 50 mL). Combined organic layer was washed with brine (20 mL) and dried over sodium sulfate. Removal of solvent under reduced pressure gave crude which was purified by reverse phase column chromatography to afford the desired product (10 mg, 9%) as off white solid.
  • Step 2 Synthesis of 6-(1-methyl-1H-benzo[d]imidazol-5-yl)-7-phenyl-1,8-naphthyridin-4(1H)-one
  • reaction mixture was cooled to RT, diluted with water (20 mL) and extracted with ethyl acetate (2 ⁇ 50 mL). Combined organic layer was washed with brine (20 mL) and dried over sodium sulfate. Removal of solvent under reduced pressure gave crude which was purified by reverse phase column chromatography to afford the desired product (3 mg 10%) as a light brown solid.
  • the reaction mixture was diluted with water (50 mL) and extracted using ethyl acetate (2 ⁇ 50 mL). The separated organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography to afford the desired product (350 mg, 26%).
  • Step 5 Synthesis of 1-(2-amino-6-(5-methylfuran-2-yl)-5-(quinolin-6-yl)pyridin-3-yl)ethanone
  • the reaction mixture was diluted with water (50 mL) and extracted using ethyl acetate (2 ⁇ 50 mL). The separated organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography to afford the desired product (160 mg, 69%).
  • Step 6 Synthesis of (E)-N′-(3-acetyl-6-(5-methylfuran-2-yl)-5-(quinolin-6-yl)pyridin-2-yl)-N,N-dimethylformimidamide
  • Step 7 Synthesis of 7-(5-methylfuran-2-yl)-6-(quinolin-6-yl)-1,8-naphthyridin-4(1H)-one
  • Step 1 Synthesis of 1-(6-amino-3-(quinolin-6-yl)-2,3′-bipyridin-5-yl)ethanone
  • reaction mixture was diluted with water (50 mL) and extracted using ethyl acetate (2 ⁇ 50 mL). The separated organic layer was dried over sodium sulfate and concentrated under reduced pressure, to get the desired product (200 mg) which was used as such for next step without further purification.
  • the progress of the reaction was monitored by LCMS.
  • the reaction mixture was diluted with ice cold water (25 mL) and the precipitates obtained were filtered under vacuum.
  • the residue was purified by reversed phase column chromatography to afford the desired product (10 mg, 6%).
  • Step 4 Synthesis of ethyl (E)-3-(2-amino-5-bromo-6-chloropyridin-3-yl)acrylate
  • Step 6 Synthesis of 7-chloro-6-(quinolin-6-yl)-1,8-naphthyridin-2(1H)-one
  • reaction mixture was heated at 70° C. for 16 h.
  • the reaction mixture was allowed to cool to RT and extracted using ethyl acetate (2 ⁇ 35 mL).
  • the combined organic layers were washed (brine), dried (anhydrous Na 2 SO 4 ) and concentrated under vacuum.
  • the light brown solid obtained was triturated with pentane to give the desired product (0.100 g) which was used as such for next step without further purification.
  • Step 7 Synthesis of 7-(5-methylfuran-2-yl)-6-(quinolin-6-yl)-1,8-naphthyridin-2(1H)-one
  • Step 1 Synthesis of 7-chloro-6-(quinolin-6-yl)-1,8-naphthyridin-4(1H)-one
  • the reaction mixture was diluted with ice cold water (5 mL) and extracted with ethyl acetate (3 ⁇ 30 mL). The separated organic layer was washed with water (5 ⁇ 20 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by normal phase column chromatography to get the desired product (120 mg, 47%).
  • Step-2 Synthesis of 7-(3-methyl-1H-pyrazol-1-yl)-6-(quinolin-6-yl)-1,8-naphthyridin-4(1H)-one
  • reaction mixture was diluted with water (50 mL) and extracted using ethyl acetate (2 ⁇ 50 mL). The separated organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified using Combi-flash column chromatography to afford the desired product (150 mg, 20%).
  • Step 5 Synthesis of 6-(benzo[d]thiazol-6-yl)-7-(5-methylfuran-2-yl)-1,8-naphthyridin-4(1H)-one
  • reaction was monitored by TLC and LCMS.
  • the reaction mixture was diluted with water (50 mL) and extracted using ethyl acetate (2 ⁇ 50 mL). The separated organic layer was dried over sodium sulfate and concentrated under reduced pressure.
  • the crude product was purified using reverse phase column chromatography to afford the desired product as off-white solid (14 mg, 11%).
  • Reaction mixture was allowed to cool to RT & quenched by adding aq. NaOH & extracted using ethyl acetate (3 ⁇ 100 mL) The combined organic layers were washed (brine), dried (anhydrous Na 2 SO 4 ) & concentrated under vacuum to get the solid which was purified by normal phase column chromatography to get the desired product (0.0092 g, 8%).
  • reaction mixture was heated at 100° C. for 18 h.
  • the reaction mixture was allowed to cool to RT and extracted using ethyl acetate (3 ⁇ 25 mL).
  • the combined organic layers were washed (brine), dried (anhydrous Na 2 SO 4 ) and concentrated under vacuum to get the solid residue which was purified by reversed phase column chromatography to get the desired product as off white solid (0.005 g, 3%)
  • the reaction mixture was diluted with water (50 mL) and extracted using ethyl acetate (2 ⁇ 50 mL). The separated organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by reverse phase column chromatography to afford the desired product (25 mg, 23%)
  • reaction mixture was heated at 90° C. for 4 h.
  • the reaction mixture was allowed to cool to RT and extracted using ethyl acetate (2 ⁇ 35 mL).
  • the combined organic layers were washed (brine), dried (anhydrous Na 2 SO 4 ) and concentrated under vacuum to get the solid residue which was purified by normal phase flash column chromatography (3% Methanol in DCM) to get the desired product as off white solid (0.020 g, 15%).
  • the reaction was monitored by NMR and LCMS.
  • the reaction mixture was diluted with water (50 mL) and extracted using ethyl acetate (2 ⁇ 50 mL). The separated organic layer was dried over sodium sulfate and concentrated under reduced pressure.
  • the crude product was purified by reverse phase column chromatography to afford (20 mg, 20%) as a desired product.
  • the reaction was monitored by NMR and LCMS.
  • the reaction mixture was diluted with water (50 mL) and extracted using ethyl acetate (2 ⁇ 50 mL). The separated organic layer was dried over sodium sulfate and concentrated under reduced pressure.
  • the crude product was purified by reverse phase column chromatography to afford (20 mg, 17%) as a desired product.
  • Binding of selected compounds to the adenosine A 1 , A 2A , A 2B , and A 3 receptors was tested using a binding competition assay.
  • the general protocol for the radioligand binding competition assay was as follows. Competition binding was performed in duplicate in the wells of a 96 well plate (Master Block, Greiner, 786201) containing binding buffer (optimized for each receptor), membrane extracts (amount of protein/well optimized for each receptor), radiotracer (final concentration optimized for each receptor), and test compound. Nonspecific binding was determined by co-incubation with 200-fold excess of cold competitor. The samples were incubated in a final volume of 0.1 mL at 25° C. for 60 minutes and then filtered over filter plates. Filters were washed six times with 0.5 mL of ice-cold washing buffer (optimized for each receptor) and 50 ⁇ L of Microscint 20 (Packard) were added on each filter. The filter plates were sealed, incubated 15 min on an orbital shaker and scintillation counted with a TopCount for 30 sec/filter.
  • GF/C filters Perkin Elmer, 6005174
  • Filters were washed six times with 0.5 mL of ice-cold washing buffer (50 mM Tris pH 7.4) and 50 ⁇ L of Microscint 20 (Packard) was added in each well. The plates were then incubated for 15 min on an orbital shaker and then counted with a TopCountTM for 1 min/well.
  • adenosine A 1 radioligand binding competition assay For the adenosine A 1 radioligand binding competition assay, a similar procedure was used except that the following reagents were used: CHO-K1-A1 cell membranes; binding buffer comprising HEPES 25 mM pH 7.4, MgCl 2 5 mM, CaCl 2 1 mM, NaCl 100 mM, saponin 10 g/mL; wash buffer comprising HEPES 25 mM pH 7.4, MgCl 2 5 mM, CaCl 2 1 mM, NaCl 100 mM; Unifilter GF/B—treated for 2 h with 0.5% PEI was the filter; and 1.6 nM of 3 H-DPCPX was the tracer.
  • binding buffer comprising HEPES 25 mM pH 7.4, MgCl 2 5 mM, CaCl 2 1 mM, NaCl 100 mM, saponin 10 g/mL
  • wash buffer comprising HEPES
  • HEK-293-A2b cell membranes 20 ⁇ g/well, preincubated 30 min at RT with g/mL Adenosine Deaminase; a binding buffer comprising HEPES 10 mM pH7.4, EDTA 1 mM, 0.5% BSA; a wash buffer comprising HEPES 10 mM pH7.4, EDTA 1 mM; a Unifilter GF/C—treated for 2 h with 0.5% PEI; and 10 nM 3 H-DPCPX as the tracer.
  • CHO-K1-A3 cell membranes 1.5 ⁇ g/well; a binding buffer comprising HEPES 25 mM pH 7.4, MgCl 2 5 mM, CaCl 2 1 mM, 0.5% BSA; a wash buffer comprising HEPES 25 mM pH 7.4, MgCl 2 5 mM, CaCl 2 1 mM; a Unifilter GF/C—treated for 2 h with 0.5% BS; and 0.4 nM of 125 I-AB-MECA as the tracer.
  • the results of the binding assay are shown in Table B1-1 and are shown as percent residual binding at a given concentration. Percent of residual binding means binding of a compound in the presence of competitor normalized to the amount of binding in the absence of competitor.
  • the compounds tested showed a range of binding to the adenosine receptors tested.
  • compound 1 strongly bound to A 2A (30% residual binding at a concentration of 100 nM), A 1 ( ⁇ 3% residual binding at 300 nM) and A 2B , ( ⁇ 9% residual binding at 300 nM) but weakly bound to A 3 (96% residual binding at 300 nM).
  • the functional activity of compounds was tested using one of the two assays to detect the present of cAMP.
  • Activation of G-protein coupled receptors results in activation of adenylcyclase which converts ATP into cAMP which is used as a downstream signaling molecule. Therefore, molecules which act as GPCR (or specifically A 2A receptor) antagonists cause a decrease in intracellular cAMP concentration.
  • Assay 2 100 nL of test articles at 100 ⁇ of final concentration were transferred to assay plate by Echo. Cells were washed twice with 5 mL of PBS 10 ⁇ L of cells were mixed with 5 mL PBS. After aspirating the PBS and adding 1.5 mL versine, cells were incubated at 37° C. for 2-5 min. After centrifugation, 4 mL of medium was added and adjusted cell density to 5,000 cells/well with stimulation buffer. 10 ⁇ L of cells were aliquoted to the assay plate, centrifuged at 1000 rpm for 1 minute, and incubated for 60 minutes at room temperature. 5 ⁇ L 4 ⁇ Eu-cAMP tracer solution and 5 ⁇ L 4 ⁇ UlightTM-anti-cAMP solution were added to assay plate, followed by centrifugation and 60-minute incubation at room temperature. Plates were read on EnVision.
  • Example B4 Human T Cell Activation Assay
  • the tumor sizes are used for the calculations of both tumor growth inhibition (TGI) and T/C values.
  • TGI tumor growth inhibition
  • the termination endpoint e.g., with TV>1000 mm 3
  • the mouse are euthanized.
  • the time from inoculation to the termination are deemed as its survival time. Survival curve are plotted by Kaplan-Meier method.
  • plasma and tumor samples are collected to explore biomarkers.

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